Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients

Genomic Restructuring in the Tasmanian Devil Facial Tumour: Chromosome Painting and Gene Mapping Provide Clues to Evolution of a Transmissible Tumour

Devil facial tumour disease (DFTD) is a fatal, transmissible malignancy that threatens the world's largest marsupial carnivore, the Tasmanian devil, with extinction. First recognised in 1996, DFTD has had a catastrophic effect on wild devil numbers, and intense research efforts to understand and contain the disease have since demonstrated that the tumour is a clonal cell line transmitted by allograft. We used chromosome painting and gene mapping to deconstruct the DFTD karyotype and determine the chromosome and gene rearrangements involved in carcinogenesis. Chromosome painting on three different DFTD tumour strains determined the origins of marker chromosomes and provided a general overview of the rearrangement in DFTD karyotypes. Mapping of 105 BAC clones by fluorescence in situ hybridisation provided a finer level of resolution of genome rearrangements in DFTD strains. Our findings demonstrate that only limited regions of the genome, mainly chromosomes 1 and X, are rearranged in DFTD. Regions rearranged in DFTD are also highly rearranged between different marsupials. Differences between strains are limited, reflecting the unusually stable nature of DFTD. Finally, our detailed maps of both the devil and tumour karyotypes provide a physical framework for future genomic investigations into DFTD

Exploring the motivators and blockers in second year undergraduate students: an ecological system approach

© 2020, The Australian Association for Research in Education, Inc. This study explored second year undergraduates’ academic motivators and blockers at multiple ecological system levels. A total of 47 second year undergraduate students from Engineering, Nursing and Psychology in an Australian city university took part in participant-led interviews regarding their academic experience beyond their foundational semester. Using an ecological system approach as the overarching theoretical framework, Tinto’s model of student retention/persistence and Self-Determination Theory (SDT) were merged within this framework to identify potential motivators and blockers across individual, microsystem, mesosystem and macrosystem levels. Results revealed that academic motivators and blockers existed at multiple ecological levels and wielded direct as well as indirect impacts on student persistence. Cohort and context-specific challenges were also identified and this demonstrated the need to better understand the contributions of an ecological approach to student persistence experience

The effect of common reductions in letter size and contrast on accommodation responses in young adult myopes and emmetropes

PURPOSE: Accommodation errors during reading and the subsequent near work-induced transient myopia (NITM) that occurs have been implicated in the development and progression of myopia. This study investigated the effects of two letter variables, size and contrast, on accommodation accuracy during the near task and on NITM and its subsequent decay. These were varied so as to mimic what might occur when students photocopy and reduce reading materials. METHODS: Based on their refractive errors, young adult subjects (18-25 years) were classified into three groups: emmetropes (n = 19), stable myopes (n = 17), and progressing myopes (n = 17). Three print sizes (N4, N6, and N8) and two print contrasts (90% and 60%) were used to give six different reading targets. Targets were presented in random order at 25 cm (4 D demand) and the text read for comprehension for 3 minutes. For each target, accommodation accuracy and NITM and its decay were measured using the free space Shin-Nippon SRW-5000 autorefractor. RESULTS: When data for all subjects were pooled, there was a significant effect of letter size (p = 0.030) but not contrast (p = 0.898) on accommodation accuracy; however, differences were small and unlikely to be clinically relevant. NITM (p = 0.033) and its decay (p = 0.012) also varied with letter size. NITM was greater and decay longer for larger letters. We found no effect of refractive error group on accommodation accuracy. In contrast, there was a significant difference in the magnitude of NITM and its decay for emmetropic and myopic subjects (although no effect of progression status); myopes had larger NITM values and longer decay times to baseline than emmetropes (NITM myopes: 0.37 +/- 0.14D vs. emmetropes: 0.19 +/- 0.17 D, p = 0.005; decay time myopes: 15.12 +/- 6.58 seconds vs. emmetropes 7.10 +/- 4.82 seconds, p = 0.0045). The differences in NITM and its decay between the two refractive groups were of similar magnitude for all six combinations of letter size and contrast. CONCLUSIONS: Our data do not support the suggestion that common reductions in letter size or contrast of reading material (as might occur for photocopied reading materials) cause greater accommodation inaccuracy and greater near work-induced adaptation effects that would exacerbate myopia development in young adults

An Australian Consensus on Infant Feeding Guidelines to Prevent Food Allergy:Outcomes From the Australian Infant Feeding Summit

Infant feeding in the first postnatal year of life has an important role in an infant's risk of developing food allergy. Consumer infant feeding advice is diverse and lacks consistency.The Australian Infant Feeding Summit was held with the aim of achieving national consensus on the wording of guidelines for infant feeding and allergy prevention.Two meetings were hosted by the Centre for Food and Allergy Research, the Australasian Society of Clinical Immunology and Allergy, and the Australian National Allergy Strategy. The first meeting of 30 allergy researchers, clinicians, and consumers assessed the evidence. The second consensus meeting involved 46 expert stakeholders including state and federal health care agencies, consumers, and experts in allergy, infant feeding, and population health.Partner stakeholders agreed on consensus wording for infant feeding advice: CONCLUSIONS: Consensus was achieved in a context in which there is a high prevalence of food allergy. Guidelines for other countries are being updated. Provision of consistent wording related to infant feeding to reduce food allergy risk will ensure clear consumer advice

Fumagillin treatment decreases the number of inflammatory cells following monocrotaline injury.

<p>Immunohistochemistry was performed for common leukocyte antigen (CD45). CD45+ cells were quantified per high power field (hpf) as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035388#s2" target="_blank">Materials and Methods</a>. MCT injury was associated with a significant decrease in the number of CD45+ cells in the lung. Early treatment with fumagillin decreased CD45+ cells in the lung by 25% (*<i>P</i><0.05 by ANOVA, n = 3–4 animals per group).</p

Fumagillin Prevents Pulmonary Hypertension and Right Ventricular Hypertrophy in MCT-Injured Rats.

<p>Rats were injected with MCT and treated with fumagillin or vehicle control as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035388#s2" target="_blank">Materials and Methods</a>. After four weeks, animals were killed, and direct right ventricular pressure was measured (A). MCT injury significantly increased RV systolic BP, which is prevented by early, but not late, treatment with fumagillin (*<i>P</i><0.05, one-way ANOVA followed by Bonferroni's post hoc test). (B) Measurement of right ventricular mass normalized to left ventricular mass (RV/LV+S). Five weeks after MCT injury, hearts were excised, fixed in formalin, and the masses of the RV and the LV+septum were determined. MCT-injured animals treated with the vehicle exhibited a significant increase in RV mass, which was prevented in both early and late fumagillin-treated animals (*<i>P</i><0.05, ANOVA followed by Bonferroni's post-hoc test).</p

Quantification of Ki67 Staining in Rat Pulmonary Arteries.

<p>Immunohistochemistry for Ki67 was performed on rat lung sections from animals injured with MCT treated with or without fumagillin. Images of pulmonary arteries are shown (A) uninjured + vehicle (B) uninjured + fumagillin (C) MCT + vehicle and (D) MCT + fumagillin (Magnification ×400, bar = 20 µm). Black arrows point to Ki67+ nuclei in the medial layer of pulmonary arteries and yellow arrows point to Ki67+ nuclei in endothelial cells. Magnification ×400, inset line 20 mm. (E) Ki67+ nuclei in the medial layer (n = 4–6 per group) and (F) Ki67+ nuclei in endothelial cells of the pulmonary arteries (n = 4 per group) were quantified per hpf as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035388#s2" target="_blank">Materials and Methods</a>. MCT injury resulted in a nearly 15-fold increase in the number of Ki67+ nuclei in medial cells per vessel per hpf in the MCT-injured vehicle-treated lung. The increase in the number of Ki67+ nuclei was decreased nearly 30% with fumagillin treatment, but this difference did not reach statistical significance. Similarly, MCT significantly increased the number of endothelial cells staining positively for Ki67 nearly tenfold. However, no differences in the number of Ki67+ nuclei were detected after fumagillin treatment.</p