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

Formal consensus study on surgery to replace the aortic valve in adults aged 18-60 years

Objective: There is uncertainty about surgical procedures for adult patients aged 18-60 years undergoing aortic valve replacement (AVR). Options include conventional AVR (mechanical, mAVR; tissue, tAVR), the pulmonary autograft (Ross) and aortic valve neocuspidisation (Ozaki). Transcatheter treatment may be an option for selected patients. We used formal consensus methodology to make recommendations about the suitability of each procedure. Methods: A working group, supported by a patient advisory group, developed a list of clinical scenarios across seven domains (anatomy, presentation, cardiac/non-cardiac comorbidities, concurrent treatments, lifestyle, preferences). A consensus group of 12 clinicians rated the appropriateness of each surgical procedure for each scenario on a 9-point Likert scale on two separate occasions (before and after a 1-day meeting). Results: There was a consensus that each procedure was appropriate (A) or inappropriate (I) for all clinical scenarios as follows: mAVR: total 76% (57% A, 19% I); tAVR: total 68% (68% A, 0% I); Ross: total 66% (39% A, 27% I); Ozaki: total 31% (3% A, 28% I). The remainder of percentages to 100% reflects the degree of uncertainty. There was a consensus that transcatheter aortic valve implantation is appropriate for 5 of 68 (7%) of all clinical scenarios (including frailty, prohibitive surgical risk and very limited life span). Conclusions: Evidence-based expert opinion emerging from a formal consensus process indicates that besides conventional AVR options, there is a high degree of certainty about the suitability of the Ross procedure in patients aged 18-60 years. Future clinical guidelines should include the option of the Ross procedure in aortic prosthetic valve selection

Murine in vitro cellular models to better understand adipogenesis and its potential applications

Adipogenesis has been extensively studied using in vitro models of cellular differentiation, enabling long-term regulation of fat cell metabolism in human adipose tissue (AT) material. Many studies promote the idea that manipulation of this process could potentially reduce the prevalence of obesity and its related diseases. It has now become essential to understand the molecular basis of fat cell development to tackle this pandemic disease, by identifying therapeutic targets and new biomarkers. This review explores murine cell models and their applications for study of the adipogenic differentiation process in vitro. We focus on the benefits and limitations of different cell line models to aid in interpreting data and selecting a good cell line model for successful understanding of adipose biology

An assessment of a sub-tropical seagrass, Zostera muelleri, as a potential bioindicator of trace elements

Skillington, AJ ORCiD: 0000-0001-9824-0050The aim of the research was to ascertain whether the locally predominant seagrass species, Zostera muelleri, could be a potential TE bioindicator. This is was achieved by conducting two multi-factor laboratory Cu and environmental experiments and spatial and temporal field assessments. Results has shown that the seagrasses life cycle and the part of the seagrass analysed can influence the metal concentrations, which is important for interpretation of results.Associated Grant:PCIMP Co-funded Industry Scholarshi

Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation.

TGF-beta inhibits adipocyte differentiation, yet is expressed by adipocytes. The function of TGF-beta in adipogenesis, and its mechanism of action, is unknown. To address the role of TGF-beta signaling in adipocyte differentiation, we characterized the expression of the TGF-beta receptors, and the Smads which transmit or inhibit TGF-beta signals, during adipogenesis in 3T3-F442A cells. We found that the cell-surface availability of TGF-beta receptors strongly decreased as adipogenesis proceeds. Whereas mRNA levels for Smads 2, 3, and 4 were unchanged during differentiation, mRNA levels for Smads 6 and 7, which are known to inhibit TGF-beta responses, decreased severely. Dominant negative interference with TGF-beta receptor signaling, by stably expressing a truncated type II TGF-beta receptor, enhanced differentiation and decreased growth. Stable overexpression of Smad2 or Smad3 inhibited differentiation and dominant negative inhibition of Smad3 function, but not Smad2 function, enhanced adipogenesis. Increased Smad6 and Smad7 levels blocked differentiation and enhanced TGF-beta-induced responses. The inhibitory effect of Smad7 on adipocyte differentiation and its cooperation with TGF-beta was associated with the C-domain of Smad7. Our results indicate that endogenous TGF-beta signaling regulates the rate of adipogenesis, and that Smad2 and Smad3 have distinct functions in this endogenous control of differentiation. Smad6 and Smad7 act as negative regulators of adipogenesis and, even though known to inhibit TGF-beta responses, enhance the effects of TGF-beta on these cells

Rainbows over the worlds public health : determinants of health models in the past, present, and future

The need to visualise the complexity of the determinants of population health and their interactions inspired the development of the rainbow model. In this commentary we chronicle how variations of this model have emerged, including the initial models of Haglund and Svanstrom (1982), Dahlgren and Whitehead (1991), and the ostgota model (2014), and we illustrate how these models have been influential in both public health and beyond. All these models have strong Nordic connections and are thus an important Nordic contribution to public health. Further, these models have underpinned and facilitated other examples of Nordic leadership in public health, including practical efforts to address health inequalities and design new health policy approaches. Apart from documenting the emergence of rainbow models and their wide range of contemporary uses, we examine a range of criticisms levelled at these models - including limitations in methodological development and in scope. We propose the time is ripe for an updated generic determinants of health model, one that elucidates and preserves the core value in older models, while recognising the developments that have occurred over the past decades in our understanding of the determinants of health. We conclude with an example of a generic model that fulfills the general purposes of a determinants of health model while maintaining the necessary scope for further adjustments to be made in the future, as well as adjustments to location or context-specific purposes, in education, research, health promotion and beyond

The Ross procedure using autologous support of the pulmonary autograft: Techniques and late results

Objectives: It is hypothesized that by performing radical aortic root manipulation and then autologous support for the pulmonary autograft in the Ross procedure, this will maintain aortic root size and should, in turn, lead to the demonstrated low incidence of late aortic regurgitation and need for reoperation on the aortic root and valve. Methods: Aortic root size was measured echocardiographically both preoperatively and then at second yearly intervals in 322 consecutive patients who underwent a Ross operation between October 1992 and June 2013 with autologous support of the pulmonary autograft root using the patient's own aorta. This technique, a variant of the inclusion cylinder method, has been developed with the aim of minimizing prosthetic materials in the aortic root. Results: Measures to reduce aortic root size included annulus reduction in 201 patients (62.4%) and reduction in aortic sinus or sinotubular junction in 159 patients (49.4%). Maximal aortic root diameter postoperatively at 5, 10, and 15 years was 34.0, 34.6, and 34.7 mm, respectively. Eleven reoperations were required during the study period for progressive aortic regurgitation (none for aortic root enlargement), with freedom from reoperation being 96% at both 15 years and 18 years. Preoperative pure aortic regurgitation, aortic annulus, and sinotubular junction enlargement were risk factors for reoperation. Conclusions: This inclusion method of pulmonary autograft implantation leads to minimal increases in aortic root size over time, with no reoperations for aortic root dilatation and a low requirement for aortic valve reoperation. The Ross procedure deserves to remain on the surgical menu for aortic valve replacement

Twenty-Year Analysis of Autologous Support of the Pulmonary Autograft in the Ross Procedure

Background. The Ross procedure is seldom offered to adults less than 60 years of age who require aortic valve replacement except in a few high-volume centers with documented expertise. Inserting the pulmonary autograft as an unsupported root replacement may lead to increasing reoperations on the aortic valve in the second decade. Methods. Of 333 patients undergoing the Ross procedure between October 1992 and June 2012, the study group of 310 consecutive patients (mean age +/- standard deviation, 39.3 +/- 12.7 years (limits 16-63) had the aortic root size adjusted to match the pulmonary autograft, which was inserted as a root replacement, with the aorta closed up around it to provide autologous support. Results. The mean follow-up time was 9.4 years; the actuarial survival was 97% at 16 years; and freedom from the composite of all reoperations on the aortic valve and late echocardiographic-detected aortic regurgitation greater than mild was 95% at 5 years, 94% at 10 years, and 93% at 15 years. Overall freedom from all reoperations on aortic and pulmonary valves was 97% at 5 years, 94% at 10 years, and 93% at 15 years. All results were better for the patients presenting with predominant aortic s Conclusions. Autologous support of the pulmonary autograft leads to excellent results in the groups presenting with aortic stenosis and mixed aortic stenosis/regurgitation and to good results for those presenting with pure aortic regurgitation. The Ross procedure, using one of the proven, durable techniques available, should be considered for more widespread adoption. (C) 2013 by The Society of Thoracic Surgeon