Second Victim Experiences of Health Care Learners and the Influence of the Training Environment on Postevent Adaptation.

Objective: To investigate the experience of medical and graduate learners with second victim experience (SVE) after medical errors or adverse patient outcomes, including impact on training and identification of factors that shape their postevent recovery. Patients and Methods: The validated Second Victim Experience and Support Tool-Revised (SVEST-R), Physician Well-Being Index, and supplemental open-ended questions were administered to multidisciplinary health care learners between April 8, 2022, and May 30, 2022, across a large academic health institution. Open-ended responses were qualitatively analyzed for iterative themes related to impact of SVE on the training experience. Results: Of the 206 survey respondents, 144 answered at least 1 open-ended question, with 62.1% (n=91) reporting at least 1 SVE. Participants discussed a wide range of SVEs and indicated that their postevent response was influenced by their training environment. Lack of support from supervisors and staff exacerbated high stress situations. Some trainees felt blamed and unsupported after a traumatic experience. Others emphasized that positive training experiences and supportive supervisors helped them grow and regain confidence. Learners described postevent processing strategies helpful to their recovery. Some, however, felt disincentivized from seeking support. Conclusion: This multidisciplinary study of learners found that the training environment was influential in postevent recovery. Our findings support the need for the inclusion of education on SVEs and adaptive coping mechanisms as part of health care professional educational curriculums. Educators and health care staff may benefit from enhanced education on best practices to support trainees after stressful or traumatic patient events.

Psychological reactance, misinformation, and distrust: A mixed methods analysis of COVID-19 vaccine uptake.

Background: Assessing perceptions of the COVID-19 vaccines is essential for understanding vaccine hesitancy and for improving uptake during public health emergencies. In the complicated landscape of COVID-19 vaccine mandates and rampant misinformation, many individuals faced challenges during vaccination decision-making. The purpose of our mixed methods study is to elucidate factors affecting vaccine decision-making and to highlight the discourse surrounding the COVID-19 vaccines in diverse and underserved communities. Methods: This mixed methods study was conducted in Arizona, Florida, Minnesota, and Wisconsin between March and November 2021, combining a cross-sectional survey (n = 3593) and focus groups (n = 47). Results: The groups least likely to report receiving a vaccination were non-Hispanic Whites, Indigenous people, males, and those with moderate socioeconomic status (SES). Those indicating high and low SES reported similar vaccination uptake. Focus group data highlighted resistance to mandates, distrust, misinformation, and concerns about the rapid development surrounding the COVID-19 vaccines. Psychological reactance theory posits that strongly persuasive messaging and social pressure can be perceived as a threat to freedom, encouraging an individual to take action to restore that freedom. Conclusion: Our findings indicate that a subsection of participants felt pressured to get the vaccine, which led to weaker intentions to vaccinate. These results suggest that vaccine rollout strategies should be reevaluated to improve and facilitate informed decision-making.

Rapid Expansion of the Healing Emotional Lives of Peers Program During COVID-19: A Second Victim Peer Support Program for Healthcare Professionals.

OBJECTIVES: In 2018, the Healing Emotional Lives of Peers (HELP) Program was implemented at Mayo Clinic Rochester to guide healthcare professionals (HCPs) after a second victim experience, such as adverse patient events or medical errors. The HELP program was expanded to all HCPs in response to the anticipated stressors of the COVID-19 pandemic. This article aims to describe the rapid expansion of the peer support program and evaluate the effectiveness of peer support provided to affected colleagues (ACs). METHODS: Quantitative data collected from workshop evaluations, activations, and associated metrics ( TPS Self-Assessment , Encounter Form , and AC Self-Assessment ) were summarized through standard descriptive statistics using SAS version 9.4 software. Open-ended responses were qualitatively analyzed for iterative themes about the HELP program and associated workshops. RESULTS: Between April 2020 and December 2021, 22 virtual workshops to train peer supporters were conducted with 827 attendees. Of these, 464 employees completed the workshop evaluation. A total of 94.2% rated the workshop as excellent or very good. Participants perceived the workshop to be highly effective and felt more prepared to support ACs. Between May 2020 and December 2021, 247 activations were submitted through the HELP Program's intranet Web site and peer support was requested for 649 employees. Of the 268 TPS Self-Assessments , 226 (84.3%) felt that they provided helpful support to an AC. One hundred ACs evaluated support received, with 93% being "extremely" or "very satisfied." Affected colleagues appreciated having a TPS provide judgment-free support. CONCLUSIONS: The HELP Program promotes a culture of safety by helping HCPs process traumatic events. To effectively meet the needs of patients, healthcare organizations need to prioritize the well-being of their employees through interpersonal support.

Characterization of direct oral anticoagulants use in adult hematopoietic stem cell transplant recipients.

Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) treatment are of interest in oncology due to ease of administration and lack of need for therapeutic monitoring compared to other anticoagulants. Data supporting their use in patients with hematologic malignancies post-hematopoietic stem cell transplant (HCT) are limited. The purpose of the study is to characterize DOAC use in HCT patients. This multicenter, retrospective cohort analysis included allogeneic and autologous HCT recipients. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB)/minor bleeding and VTE recurrence. Of 126 patients, 91 (72.2%) patients received an autologous HCT, and 35 (27.8%) patients received an allo-HCT. No major bleeding occurred in either transplant recipient groups. In autologous HCT recipients, CRNMB/minor bleeding occurred in four (4.4%) patients and VTE recurrence occurred in one (1.1%) patient. For allogeneic HCT recipients, CRNMB/minor bleeding occurred in five (14.3%) patients and VTE recurrence occurred in two (5.7%) patients. For patients that experienced a CRNMB, five (100%) of the allogeneic HCT and two (50%) of the autologous HCT recipients were thrombocytopenic at the time of bleeding. Only 38.5% of patients who experienced a drug-drug interaction requiring DOAC dose adjustment received the appropriate dose adjustment. DOACs were associated with low rates of recurrent VTE and no major bleeding events, similar to published data on DOAC use in the general cancer patient population. This suggests that DOACs may be safe therapeutic options with proactive management of drug interactions and careful monitoring for bleeding events, especially in the allogeneic HCT population where minor bleeding rates were slightly higher.

Influence of the COVID-19 pandemic on prenatal and postpartum patient experiences and well-being.

BACKGROUND: It has yet to be fully elucidated how differing populations of obstetric patients adapted to the disruptions in perinatal care and postpartum support from the COVID-19 pandemic. We surveyed an enriched sample of socioeconomically advantaged patients to understand the influence of COVID-19 on their perinatal care experience, well-being, and coping. METHODS: We surveyed pregnant and postpartum patients (n = 6140) at a large academic medical center in the Midwest of the United States using the Coronavirus and Perinatal Experiences instrument in Spring 2021. RESULTS: The survey was sent to 6141 pregnant and postpartum patients; 1180 (17.8%) respondents completed the survey, including 256 who were pregnant and 834 postpartum. Most pregnant patients experienced no changes in their prenatal care with 16.5% indicating somewhat worsened care. In the postpartum cohort, 37.5% stated their care had somewhat worsened. In describing influences on stress and mental health, 58.1% of postpartum respondents stated it was moderately, and 17.4% significantly, worse. The pandemic had a somewhat or moderately negative influence for 72.7% of respondents, with 11.0% stating these effects were extremely negative. Both cohorts characterized a range of coping strategies, most commonly, talking with friends and family (76.3%). CONCLUSION(S): Even among this sample of socioeconomically advantaged patients, respondents indicated that the pandemic disrupted many facets of their medical care and daily life, especially social activities and postpartum support. Our findings suggest that counseling on coping and adaptation strategies for stressors and increased health systems support be part of perinatal care during public health emergencies for all demographic groups.

Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.

Teaching the Teacher: Novel Faculty Development for VA Hospitalists.

Background: The US Department of Veterans Affairs (VA) is the largest educator of health professions trainees in the country, but the roles and responsibilities of the modern clinician educator are increasingly challenging and complex. Most VA academic hospitalists with access to professional and faculty development receive it through academic affiliates. Many VA hospitalists lack this option, and teaching within the VA is unique given its specific health system, clinical environments, and patient population. Observations: Teaching the Teacher is a facilitation-based educational series for inpatient hospitalists at VA medical centers that is tailored to self-reported needs and provides faculty development through the lens of VA medicine. The transition from in-person to synchronous virtual programming allowed for wider dissemination of the program, and to date, 10 VA hospitalist sections across the country have participated in the series. Conclusions: VA clinicians want and deserve dedicated training to optimize their confidence and skills in their roles as health professions educators. Teaching the Teacher is a pilot faculty development program that has met success based on its goal of meeting the specific needs of VA clinician educators in hospital medicine. It has the potential to serve as a model for clinical educator onboarding and to allow for the rapid spread of best teaching practices among clinical educators.

Perceptions and Use of Telehealth Among Diverse Communities: Multisite Community-Engaged Mixed Methods Study.

BACKGROUND: Telehealth has been increasingly adopted by health care systems since the start of the COVID-19 pandemic. Although telehealth may provide convenience for patients and clinicians, there are several barriers to accessing it and using it effectively to provide high-quality patient care. OBJECTIVE: This study was part of a larger multisite community-engaged study conducted to understand the impact of COVID-19 on diverse communities. The work described here explored the perceptions of and experience with telehealth use among diverse and underserved community members during COVID-19. METHODS: We used mixed methods across three regions in the United States (Midwest, Arizona, and Florida) from January to November 2021. We promoted our study through social media and community partnerships, disseminating flyers in English and Spanish. We developed a moderator guide and conducted focus groups in English and Spanish, mostly using a videoconferencing platform. Participants were placed in focus groups with others who shared similar demographic attributes and geographic location. Focus groups were audio-recorded and transcribed. We analyzed our qualitative data using the framework analytic approach. We developed our broader survey using validated scales and with input from community and scientific leaders, which was then distributed through social media in both English and Spanish. We included a previously published questionnaire that had been used to assess perceptions about telehealth among patients with HIV. We analyzed our quantitative data using SAS software and standard statistical approaches. We examined the effect of region, age, ethnicity/race, and education on the use and perceptions of telehealth. RESULTS: We included data from 47 focus groups. Owing to our mode of dissemination, we were not able to calculate a response rate for the survey. However, we received 3447 English-language and 146 Spanish-language responses. Over 90% of participants had internet access and 94% had used telehealth. Approximately half of all participants agreed or strongly agreed that telehealth would be beneficial in the future because it better fit their schedules and they would not need to travel. However, approximately half of the participants also agreed or strongly agreed they would not be able to express themselves well and could not be examined when using telehealth. Indigenous participants were especially concerned about these issues when compared to other racial groups. CONCLUSIONS: This work describes findings from a mixed methods community-engaged research study about telehealth, including perceived benefits and concerns. Although participants enjoyed the benefits of telehealth (eg, not having to travel and easier scheduling), they also had concerns (eg, not being able to express themselves well and not having a physical exam) about telehealth. These sentiments were especially notable among the Indigenous population. Our work highlights the importance of fully understanding the impact of these novel health delivery modalities on the patient experience and actual or perceived quality of care received.

Key Stakeholder Perspectives of Community Engagement Efforts and the Impact of the Covid-19 Pandemic.

INTRODUCTION: The COVID-19 pandemic has disproportionally affected historically marginalized populations and their access to resources and healthcare. In times of crisis, authentic community engagement is more important than ever. This study was Phase 1 of a larger 3-phase study to conduct timely community-engaged research with community members to understand the disproportionate impact of COVID-19 on historically underserved communities. The objective of this work was to conduct key informant (KI) interviews (1) to understand community organizations perspectives about the role that large academic health centers play as they interface with community organizations to support their work, (2) to leverage KI's expertise to identify needs and assets within the community, and (3) to inform both Phase 2 (focus group qualitative research) and Phase 3 (survey) of the broader study. METHODS: A total of 24 key informants were identified through purposeful sampling and one-on-one semi-structured interviews were conducted across 4 states using video conferencing. RESULTS: Barriers to access and lack of transparency were highlighted as major issues requiring reform-in particular, aggressive billing practices and insurance barriers exacerbated local distrust of medical institutions. KIs recognized the health institution's support for testing and vaccination during the COVID-19 pandemic, but noted other significant gaps in care, especially regarding mental health support. Although communication with the health institution was consistent for some KIs, others experienced unsustained communication efforts that hindered cooperation and relationship building. CONCLUSIONS: Leaders in the community as key stakeholders can provide unique insights into the challenges and potential solutions required to promote health equity, and foster understanding between local communities and healthcare institutions.

Epo-IGF1R cross talk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm.

We found that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with colony-forming unit-erythroid (CFU-E) activity (stress CFU-E [sCFU-E]) is expanded markedly to restore the erythron. sCFU-E cells are targets of erythropoietin (Epo), and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2- and STAT5-dependent expression of IRS2, thus engaging the progrowth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R and IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR-lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant JAK2(V617F) in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In samples from patients with myeloproliferative neoplasm, the number of sCFU-E-like cells increases, and inhibition of IGR1R and IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identified a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.

"I had so many life-changing decisions I had to make without support": a qualitative analysis of women's pregnant and postpartum experiences during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has posed profound challenges for pregnant patients and their families. Studies conducted early in the pandemic found that pregnant individuals reported increased mental health concerns in response to pandemic-related stress. Many obstetric practices changed their healthcare delivery models, further impacting the experiences of pregnant patients. We conducted a survey study to explore the ways in which COVID-19 impacted the lives of pregnant and newly postpartum people. METHODS: A mixed-methods survey was distributed to all patients ≥18 years old who were pregnant between January 1st, 2020 - April 28, 2021 in a large Midwest health system. Open-ended survey responses were analyzed for common themes using standard qualitative methodology. RESULTS: Among the 1182 survey respondents, 647 women provided an open-ended response. Of these, 77% were in the postpartum period. The majority of respondents identified as white, were partnered or married, and owned their own home. Respondents reported feeling greater uncertainty, social isolation, as though they had limited social and practical support, and negative mental health effects as a result of the pandemic. Many cited sudden or arbitrary changes to their medical care as a contributing factor. Though in the minority, some respondents also reported benefits from the changes to daily life, including perceived improvements to medical care, better work-life balance, and opportunities for new perspectives. CONCLUSIONS: This large qualitative dataset provides insight into how healthcare policy and lifestyle changes impacted pregnant and postpartum people. Respondents expressed similar levels of uncertainty and mental health concerns compared to other cohorts but less overall positivity. Our findings suggest greater attention be given to the impact of pandemic-related stress on pregnant and postpartum women. As the pandemic continues, these data identify areas where investment in additional support may have the greatest impact.

Pregnant and Postpartum Patients' Views of COVID-19 Vaccination.

Perinatal patients were faced with the decision to receive a COVID-19 vaccination in the absence of clinical trial data on COVID-19 vaccine safety and efficacy in pregnant and lactating patients. We used the Coronavirus Perinatal Experiences Impact Survey to explore the impact of the COVID-19 pandemic on the lives of perinatal patients. The mixed-method survey was distributed to all patients ≥ 18 years old who were pregnant between January 1st, 2020 - April 28, 2021 at a large academic health system in the upper Midwest. Open-ended responses were qualitatively analyzed. Of the 1182 respondents who completed the survey, 647 answered at least one open-ended question. Among these 647 participants, 85 discussed COVID-19 vaccination and were secondarily analyzed. The responses illustrated a wide range of perspectives regarding COVID-19 vaccination, with many citing concerns over the consequences of maternal vaccination on their child. Others highlighted the lack of information surrounding COVID-19 vaccination in perinatal women. Respondents also discussed challenges discussing their vaccination status with their healthcare provider and the impact of family member's vaccination decisions on postpartum support and childcare. The unprompted discussion of concerns about COVID-19 vaccination suggests this decision weighed on many participants, especially in the context of lack of information early in the pandemic. Our findings support the need for open discussion of perinatal patients with their providers on COVID-19 vaccination during the pregnancy and postpartum period.

Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti-activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1's activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.

MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation.

Mitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

Erythropoietin regulation of red blood cell production: from bench to bedside and back.

More than 50 years of efforts to identify the major cytokine responsible for red blood cell (RBC) production (erythropoiesis) led to the identification of erythropoietin (EPO) in 1977 and its receptor (EPOR) in 1989, followed by three decades of rich scientific discovery. We now know that an elaborate oxygen-sensing mechanism regulates the production of EPO, which in turn promotes the maturation and survival of erythroid progenitors. Engagement of the EPOR by EPO activates three interconnected signaling pathways that drive RBC production via diverse downstream effectors and simultaneously trigger negative feedback loops to suppress signaling activity. Together, the finely tuned mechanisms that drive endogenous EPO production and facilitate its downstream activities have evolved to maintain RBC levels in a narrow physiological range and to respond rapidly to erythropoietic stresses such as hypoxia or blood loss. Examination of these pathways has elucidated the genetics of numerous inherited and acquired disorders associated with deficient or excessive RBC production and generated valuable drugs to treat anemia, including recombinant human EPO and more recently the prolyl hydroxylase inhibitors, which act partly by stimulating endogenous EPO synthesis. Ongoing structure-function studies of the EPOR and its essential partner, tyrosine kinase JAK2, suggest that it may be possible to generate new "designer" drugs that control selected subsets of cytokine receptor activities for therapeutic manipulation of hematopoiesis and treatment of blood cancers.

Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9.

BACKGROUND: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/ß-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear. METHODS: We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs). FINDINGS: We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/ß-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML. INTERPRETATION: By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/ß-catenin-dependent growth of LICs. Small molecules disrupting WNT/ß-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.

Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a "U-shaped" relationship.

The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.

Dynamic Change of Transcription Pausing through Modulating NELF Protein Stability Regulates Granulocytic Differentiation.

The NELF complex is a metazoan-specific factor essential for establishing transcription pausing. Although NELF has been implicated in cell fate regulation, the cellular regulation of NELF and its intrinsic role in specific lineage differentiation remains largely unknown. Using mammalian hematopoietic differentiation as a model system, here we identified a dynamic change of NELF-mediated transcription pausing as a novel mechanism regulating hematopoietic differentiation. We found a sharp decrease of NELF protein abundance upon granulocytic differentiation and a subsequent genome-wide reduction of transcription pausing. This loss of pausing coincides with activation of granulocyte-affiliated genes and diminished expression of progenitor markers. Functional studies revealed that sustained expression of NELF inhibits granulocytic differentiation, whereas NELF depletion in progenitor cells leads to premature differentiation towards the granulocytic lineage. Our results thus uncover a previously unrecognized regulation of transcription pausing by modulating NELF protein abundance to control cellular differentiation.