Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1α signaling pathway in liver inflammatory injury.

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays important roles in regulating immune and metabolic homeostasis. Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) transcription factors are crucial for the regulation of immune cell function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1α activity, leading to Foxp3 downregulation and RORγt and IL-17A upregulation in IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1α and upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. Silencing of HIF-1α in ATF3 KO mice ameliorated IRI-induced liver damage in parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1α signaling, which was crucial for the modulation of TLR4-driven inflammatory responses and T cell development. The present study provides potential therapeutic targets for the treatment of liver IRI followed by liver transplantation

Group 2 Innate Lymphoid Cells Are Redundant in Experimental Renal Ischemia-Reperfusion Injury.

Acute kidney injury (AKI) can be fatal and is a well-defined risk factor for the development of chronic kidney disease. Group 2 innate lymphoid cells (ILC2s) are innate producers of type-2 cytokines and are critical regulators of homeostasis in peripheral organs. However, our knowledge of their function in the kidney is relatively limited. Recent evidence suggests that increasing ILC2 numbers by systemic administration of recombinant interleukin (IL)-25 or IL-33 protects against renal injury. Whilst ILC2s can be induced to protect against ischemic- or chemical-induced AKI, the impact of ILC2 deficiency or depletion on the severity of renal injury is unknown. Firstly, the phenotype and location of ILC2s in the kidney was assessed under homeostatic conditions. Kidney ILC2s constitutively expressed high levels of IL-5 and were located in close proximity to the renal vasculature. To test the functional role of ILC2s in the kidney, an experimental model of renal ischemia-reperfusion injury (IRI) was used and the severity of injury was assessed in wild-type, ILC2-reduced, ILC2-deficient, and ILC2-depleted mice. Surprisingly, there were no differences in histopathology, collagen deposition or mRNA expression of injury-associated (Lcn2), inflammatory (Cxcl1, Cxcl2, and Tnf) or extracellular matrix (Col1a1, Fn1) factors following IRI in the absence of ILC2s. These data suggest the absence of ILC2s does not alter the severity of renal injury, suggesting possible redundancy. Therefore, other mechanisms of type 2-mediated immune cell activation likely compensate in the absence of ILC2s. Hence, a loss of ILC2s is unlikely to increase susceptibility to, or severity of AKI

Fidelity Assessment in Community Programs: An Approach to Validating Simplified Methodology.

Fidelity to intervention protocol is linked to best outcomes for individuals with autism spectrum disorder (ASD; see Boyd & Corley [Autism 5(4):430-441, 2001]; Pellecchia et al. [J Autism Dev Disord 45(9):2917-2927, 2015]); however, fidelity measurement tools that are both accurate and feasible for community use are often not available. In this paper we explore methods for validated simplification of fidelity assessment procedures toward the goal of increased use in clinical practice. Video recordings (n = 36) of therapists working with children with ASD were coded using three variations of fidelity assessment methodology (trial-by-trial, 5-point Likert Scale, and 3-point Likert Scale), and the results were compared for exact agreement, mastery criterion agreement, and overall reliability. The results indicated overall a very high percentage of exact agreement (mean 99.44%, range 94.4-100%) and excellent reliability (mean Krippendorff's alpha [Kα] 1.0) between the trial-by-trial and 5-point Likert Scale across all components; however, the 3-point method may be viewed as being the more feasible strategy within community programs

Building capacity for dissemination and implementation research: One university’s experience

Abstract Background While dissemination and implementation (D&I) science has grown rapidly, there is an ongoing need to understand how to build and sustain capacity in individuals and institutions conducting research. There are three inter-related domains for capacity building: people, settings, and activities. Since 2008, Washington University in St. Louis has dedicated significant attention and resources toward building D&I research capacity. This paper describes our process, challenges, and lessons with the goal of informing others who may have similar aims at their own institution. Activities An informal collaborative, the Washington University Network for Dissemination and Implementation Research (WUNDIR), began with a small group and now has 49 regular members. Attendees represent a wide variety of settings and content areas and meet every 6 weeks for half-day sessions. A logic model organizes WUNDIR inputs, activities, and outcomes. A mixed-methods evaluation showed that the network has led to new professional connections and enhanced skills (e.g., grant and publication development). As one of four, ongoing, formal programs, the Dissemination and Implementation Research Core (DIRC) was our first major component of D&I infrastructure. DIRC’s mission is to accelerate the public health impact of clinical and health services research by increasing the engagement of investigators in later stages of translational research. The aims of DIRC are to advance D&I science and to develop and equip researchers with tools for D&I research. As a second formal component, the Washington University Institute for Public Health has provided significant support for D&I research through pilot projects and a small grants program. In a third set of formal programs, two R25 training grants (one in mental health and one in cancer) support post-doctoral scholars for intensive training and mentoring in D&I science. Finally, our team coordinates closely with D&I functions within research centers across the university. We share a series of challenges and potential solutions. Conclusion Our experience in developing D&I research at Washington University in St. Louis shows how significant capacity can be built in a relatively short period of time. Many of our ideas and ingredients for success can be replicated, tailored, and improved upon by others

The effect of sex on social cognition and functioning in schizophrenia

Social cognitive impairment is a core feature of schizophrenia and plays a critical role in poor community functioning in the disorder. However, our understanding of the relationship between key biological variables and social cognitive impairment in schizophrenia is limited. This study examined the effect of sex on the levels of social cognitive impairment and the relationship between social cognitive impairment and social functioning in schizophrenia. Two hundred forty-eight patients with schizophrenia (61 female) and 87 healthy controls (31 female) completed five objective measures and one subjective measure of social cognition. The objective measures included the Facial Affect Identification, Emotion in Biological Motion, Self-Referential Memory, MSCEIT Branch 4, and Empathic Accuracy tasks. The subjective measure was the Interpersonal Reactivity Index (IRI), which includes four subscales. Patients completed measures of social and non-social functional capacity and community functioning. For objective social cognitive tasks, we found a significant sex difference only on one measure, the MSCEIT Branch 4, which in both patient and control groups, females performed better than males. Regarding the IRI, females endorsed higher empathy-related items on one subscale. The moderating role of sex was found only for the association between objective social cognition and non-social functional capacity. The relationship was stronger in male patients than female patients. In this study, we found minimal evidence of a sex effect on social cognition in schizophrenia across subjective and objective measures. Sex does not appear to moderate the association between social cognition and functioning in schizophrenia

ASPIRE Flight Mechanics Modeling and Post Flight Analysis

The Advanced Supersonic Parachute Inflation Research and Experiment (ASPIRE) is a series of sounding rocket flights aimed at understanding the dynamics of supersonic parachutes that are used for Mars robotic applications. SR01 was the first sounding rocket flight of ASPIRE that occurred off the coast of Wallops Island, VA on Oct. 4, 2017 and showed the successful deployment and inflation of a Mars Science Laboratory built-to- print parachute in flight conditions similar to the 2012 Mars Science Laboratory (MSL) mission. SR02 was the second sounding rocket flight that also occurred off the coast of Wallops Island on March 31, 2018 and showcased the successful deployment and inflation of a new strengthened parachute being considered for the Mars 2020 mission at fifty percent higher dynamic pressure than observed on MSL. Prior to both flights, a multi-body flight dynamics simulation was developed to predict the parachute dynamics and was used, in conjunction with other tools, to target Mars-relevant flight conditions. After each flight, the reconstructed trajectory was used to validate the pre-flight dynamics simulation and recommend changes to improve predictions for future flights planned for the ASPIRE pro- gram. This paper describes the flight mechanics simulation and the post flight reconciliation process used to validate the flight models

고리형 디펩티드 Cyclo(His-Pro)의 신장손상 및 섬유화 개선효과와 NRF2 매개 작용기전

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 임상의과학과, 2021. 2. 김연수.급성신손상은 회복되지 못하는 경우 만성콩팥병으로 진행하며 회복을 방해하는 요인으로는 염증, 산화 스트레스, 그리고 노화와 세포 사멸 등이 있으며 이를 조절하면 신질환의 진행을 억제할 수 있을 것으로 여겨지고 있다. 최근, 활성화 된 상태에서 항염증, 항산화 효과를 나타내는 전사인자 Nuclear factor erythroid-2-related factor 2 (NRF2)는 신질환 치료의 잠재적인 목표로 고려된다. 고리형 디펩티드의 일종인 cyclo-histidine-proline (cyclo(His-Pro); CHP)는 NRF2를 활성화 시키며, 신경퇴행성질환이나 당뇨병 실험 모델에서 보호 효과를 지님이 확인되었으나 신장에 미치는 효과에 관하여는 아직 알려진 바가 없어 CHP의 신보호 효과에 관하여 알아보고자 하였다. CHP 전처치는 급성 신손상을 대변하는 신장 허혈-재관류 모델에서 염증세포의 침윤, 세포 사멸, 세뇨관 손상을 뚜렷하게 감소시켰으며, 신장 기능을 보호하였다. 신장 요세관세포를 이용한 각종 산화 스트레스 모델에서 CHP 처치는 NRF2의 전사를 증가시키고, 활성화 산소의 형성 및 세포 사멸을 억제하였다. 단일 요관 폐쇄 모델에서 예방적인 CHP 전처치 및 신손상 발생후의 치료적인 CHP 투여는 신손상을 억제하였다. 만성콩팥병 동물 모델인 5/6 신절제 쥐에서 CHP치료군은 호전된 신기능과 감소된 섬유화 소견을 보였다. 만성콩팥병을 대변하기 위하여 신장세포에 TGFβ를 처리하여 섬유화를 유발하였으며, CHP 치료는 급성 세포 실험 모델에서와 유사하게 NRF2 연관 경로의 활성화를 유발하고, 활성화산소의 형성 및 세포 사망 및 노화 그리고 부분 상피간엽 이행을 억제하였다. 엑체크로마토그래피 질량분석기를 이용하여 5/6 신절제 쥐의 혈장 및 소변의 CHP의 농도와 조직에서의 NRF2 발현을 확인하였다. 5/6 신절제 쥐 모델 및 정상 대조군에서 CHP 청소율은 크레아티닌 청소율과 양의 상관관계를 보였다. 즉 낮은 CHP 청소율이 신기능이 저하된 쥐에서 동반됨을 확인하였다. 동물 및 세포 실험의 결과를 실제 환자에 적용하기 위하여 만성 신부전 환자를 만성신부전 1, 2기/ 3기/ 4, 5기의 3군으로 나누어 혈장 및 소변에서의 CHP농도 및 NRF2 조직 발현 정도를 분석하였다. 만성 신부전이 진행함에 따라 혈장 CHP농도는 증가하여 만성 신부전 4, 5기에서 가장 높은 농도를 확인하였다. 반대로, NRF2의 조직발현은 만성신부전이 진행함에 따라 감소하는 음의 상관관계를 보였다. 만성콩팥병의 진행에 따른 내인성 혈장 CHP농도의 증가는 NRF2 경로를 활성화시켜 신장을 보호하기 위한 일종의 보상작용일 것으로 생각된다. 본 연구에서 CHP는 NRF2 경로를 활성화시켜 신장 보호 효과를 나타냄을 확인하였으며, 이를 근거로 CHP의 신질환 치료제로써의 잠재적인 가능성을 제시하여 볼 수 있을 것이다.Acute kidney injury (AKI) frequently leads to chronic kidney disease (CKD) through inflammation, oxidative stress, cell senescence and apoptosis. Due to its anti-inflammatory and anti-oxidative effects, nuclear factor-erythroid-2-related factor 2 (NRF2) could be a therapeutic target of the kidney disease. While cyclic dipeptide cyclo(His-Pro) (CHP), a known NRF2 activator, has been shown to exert protective effect against neurodegenerative diseases, its effects on renal protection has not been established. Exogenous CHP pre-treatment preserved kidney function and produced significant reduction in tubular injury, apoptosis, and inflammatory cell infiltration on ischemia-reperfusion injury (IRI) model. Compared with 5/6 nephrectomy (Nx) rat, CHP-treated 5/6 Nx rat displayed restored kidney function and pathologically improved fibrosis. In the chronic in vitro model, exogenous CHP reduces reactive oxygen species (ROS) production and cell death via the NRF2 associated pathway in concordant with acute in vitro model. CHP improved kidney injury in unilateral ureteral obstruction (UUO) model with both prophylactic and therapeutic treatment regimens. To evaluate the relationship between endogenous CHP level and CKD progression, The present study measured plasma CHP concentration, and tissue expression of NRF2 in samples from CKD patients. In sham and 5/6 nephrected kidney, CHP clearance demonstrated positive relationship with creatinine clearance. Decreased CHP clearance was reported in rats with deteriorated kidney. In CKD patients, as kidney function deteriorated, plasma CHP concentration was increased. Contrarily, tissue expression of NRF2 displayed negative relationship with CKD progression. Elevated endogenous plasma CHP levels could be considered as a compensatory processes evoked to enhance the NRF2 pathway. This study has uncovered a major protective role of CHP for kidney disease through NRF2 pathway activation that could be potentiated as a therapeutic strategy.Table of Contents ABSTRACT i LIST OF TABLES iv LIST OF FIGURES v INTRODUCTION 1 METHODS AND MATERIALS 4 RESULTS 19 DISCUSSION 33 TABLES 41 FIGURES 47 REFERENCES 112 ABSTRACT (KOREAN) 123Docto