Srebf1a is a key regulator of transcriptional control for adipogenesis

Adipogenesis is regulated by a complex cascade of transcriptional factors, but little is known about the early events that regulate the adipogenic program. Here, we report the role of the srebf1a gene in the differentiation of fibroblastic 3T3-F442A cells. We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188. Knockdown of srebf1a inhibited the adipogenic program because it blocked the expression of genes encoding PPARγ2, C/EBPα, SREBP1c and even FABP4, demonstrating that SREBP1a activation is upstream of these three essential adipogenic transcription factors. Kinetic analysis during differentiation illustrated that the order of expression of adipogenic genes was the following: cebpb, srebf1a, pparg2, cebpa, srebp1c and fabp4. Our data suggest that srebf1a acts as an essential link between the GSK3β-C/EBPβ signaling axis and the beginning of the adipogenic transcriptional cascade

Retinoic Acids Potentiate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells

As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is one of the most osteogenic BMPs. Retinoic acid (RA) signaling is known to play an important role in development, differentiation and bone metabolism. In this study, we investigate the effect of RA signaling on BMP9-induced osteogenic differentiation of mesenchymal progenitor cells (MPCs).Both primary MPCs and MPC line are used for BMP9 and RA stimulation. Recombinant adenoviruses are used to deliver BMP9, RARalpha and RXRalpha into MPCs. The in vitro osteogenic differentiation is monitored by determining the early and late osteogenic markers and matrix mineralization. Mouse perinatal limb explants and in vivo MPC implantation experiments are carried out to assess bone formation. We find that both 9CRA and ATRA effectively induce early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as osteopontin (OPN) and osteocalcin (OC). BMP9-induced osteogenic differentiation and mineralization is synergistically enhanced by 9CRA and ATRA in vitro. 9CRA and ATRA are shown to induce BMP9 expression and activate BMPR Smad-mediated transcription activity. Using mouse perinatal limb explants, we find that BMP9 and RAs act together to promote the expansion of hypertrophic chondrocyte zone at growth plate. Progenitor cell implantation studies reveal that co-expression of BMP9 and RXRalpha or RARalpha significantly increases trabecular bone and osteoid matrix formation.Our results strongly suggest that retinoid signaling may synergize with BMP9 activity in promoting osteogenic differentiation of MPCs. This knowledge should expand our understanding about how BMP9 cross-talks with other signaling pathways. Furthermore, a combination of BMP9 and retinoic acid (or its agonists) may be explored as effective bone regeneration therapeutics to treat large segmental bony defects, non-union fracture, and/or osteoporotic fracture

Northern exposure: Alaska, climate change, Indigenous rights, and atmospheric trust litigation

This chapter considers the atmospheric trust litigation in the case of Nelson Kanuk v. State of Alaska over the climate inaction of the State of the Alaska. The dispute is a compelling case study in respect of constitutional law, the public trust doctrine, climate change, intergenerational justice, Indigenous rights, and Indigenous intellectual property. The new litigation between Esau Sinnok and the State of Alaska promises to further refine and clarify issues in respect of climate change, human rights, and Indigenous interests. Such climate litigation highlights larger international legal issues in respect of Indigenous peoples and climate change. There has been debate over Indigenous rights and climate change during the discussions in respect of the United Nations Declaration on the Rights of Indigenous Peoples 2007, the Anchorage Declaration 2009, the Paris Agreement 2015, and the Bonn climate talks in 2017. In the future, no doubt Indigenous communities will seek to engage in climate litigation against governments and corporations in order to seek redress for climate injustice, as well as loss and damage

Short- and midterm outcomes of coronary artery bypass surgery performed by surgeons in training

Objective: The effect of training on outcomes in cardiac surgery is poorly studied. We aimed to study the results of coronary artery bypass grafting procedures performed by surgeons in training across our state with respect to short- and midterm postoperative outcomes. Methods: All coronary artery bypass grafting surgeries performed by trainee surgeons between July 2001 and December 2006 were compared with those performed by consultant surgeons using mandatory prospectively collected statewide data. Early mortality; prolonged ventilation or intensive care unit stay; return to operating theater for bleeding, stroke, myocardial infarction, or renal failure; and 5-year survival were compared using propensity score analysis. Results: A total of 7745 surgeries were included in this study. Trainees performed 983 (13%) surgeries. Trainee surgeries had longer perfusion and crossclamp times. Crude early postoperative outcomes were similar between trainee and consultant surgeries. After propensity score adjustment, early outcomes remained similar, with the exception of myocardial infarction (0.8% in trainee surgeries vs 0.4% in consultant surgeries, P = .046). Adjusted 1-, 3-, and 5-year survivals were similar between trainee and consultant surgeries: 95.3% versus 95.5%, 90.8% versus 92.0%, and 86.3% versus 87.1%, respectively. Conclusion: Coronary artery bypass grafting performed by trainee surgeons within a supervised program is safe with acceptable short- and midterm outcomes. © 2009 The American Association for Thoracic Surgery

Does Prior Percutaneous Coronary Intervention Adversely Affect Early and Mid-Term Survival After Coronary Artery Surgery?

Objectives: To determine the association between previous percutaneous coronary intervention (PCI) and results after coronary artery bypass graft surgery (CABG). Background: Increasing numbers of patients undergoing CABG have previously undergone PCI. Methods: We analyzed consecutive first-time isolated CABG procedures within the Australasian Society of Cardiac and Thoracic Surgeons Database from June 2001 to May 2008. Logistic regression and propensity score analyses were used to assess the risk-adjusted impact of prior PCI on in-hospital mortality and major adverse cardiac events. Cox regression model was used to assess the effect of prior PCI on mid-term survival. Results: Of 13,184 patients who underwent CABG, 11,727 had no prior PCI and 1,457 had prior PCI. Mean follow-up was 3.3 ± 2.1 years. Patients without prior PCI had a higher EuroSCORE value (4.4 ± 3.3 vs. 3.6 ± 3.0, p < 0.001), were older, and more likely to have left main stem stenosis and recent myocardial infarction. There was no difference in unadjusted in-hospital mortality (1.65% vs. 1.55%, p = 0.78) or major adverse cardiac events (3.0% vs. 3.0%, p = 0.99) between patients with or without prior PCI. After adjustment, prior PCI was not a predictor of in-hospital (odds ratio: 1.22, 95% confidence interval [CI]: 0.76 to 2.0, p = 0.41) or mid-term mortality at 6-year follow-up (hazard ratio: 0.94, 95% CI: 0.75 to 1.18, p = 0.62). Conclusions: In this large registry study, prior PCI was not associated with increased short- or mid-term mortality after CABG. Good outcomes can be obtained in the group of patients undergoing CABG who have had previous PCI. © 2009 American College of Cardiology Foundation

Organised Voluntarism in Ireland

Historically Irish society has had a long tradition of grass roots voluntary community work. However, with the rise of neoliberalism in the 1990s, the Irish community and voluntary sector became increasingly subjected to government controls and restrictions. As a result, voluntary community work became more formally organised, centrally regulated and depoliticised. Such ‘organised voluntarism’ (Fye and Mulligan in Prog Hum Geogr 27:397–413, 2003) has since become part and parcel of contemporary community development initiatives in Ireland. While some UK research has explored the impact that this discursive and policy shift is having on volunteering, there is a dearth of Irish literature on this issue. This article presents an account of how and why this form of voluntarism took hold in contemporary Ireland. The establishment of Family Resource Centres in Ireland will be recalled and assessed to further illustrate the observations being made about organised voluntarism in Ireland.</p