Heme Oxygenase-1 Deletion Affects Stress Erythropoiesis

BACKGROUND:Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis. METHODOLOGY/PRINCIPAL FINDINGS:We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations. CONCLUSIONS/SIGNIFICANCE:As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases

Horseplay, care and hands on hard work: gendered strategies of a project manager on a construction site

The discourse of managerial expertise favours rational analysis and masculine ideals but contemporary management literature also recognises the value of well-being and employee voice in the workplace. Drawing upon narrative analysis of interview data, we share unique insights into the lived experiences of Laura, one female project manager who recently managed a construction site in the Midlands in the UK. In contrast to previous research which indicates that female managers tend to conform to quite a traditional set of gender behaviours, Laura embraces a range of workplace appropriate gendered strategies, such as hard work and horseplay, together with sensitivity and caring. She draws from this mix of gendered strategies in negotiating between two different discourses of construction; one professional and one tough and practical. Her behaviour both reproduces the masculine ideals (through horseplay and heroic management) and opens up possibilities for modernising construction management (by caring). It is this combination of strategies that is at the heart of tacit expertise for Laura. Theoretically, the discussion adds to the development of a more nuanced understanding of management expertise as situated and person specific knowledge that draws on both the explicit and tacit. Specifically, the centrality of gendered strategies beyond the masculine ideals to success on site is highlighted

The influence of injection molding parameter on properties of thermally conductive plastic

Thermally conductive plastic is the composite between metal-plastic material that is becoming popular because if it special characteristic. Injection moulding was regarded as the best process for mass manufacturing of the plastic composite due to its low production cost. The objective of this research is to find the best combination of the injection parameter setting and to find the most significant factor that effect the strength and thermal conductivity of the composite. Several parameter such as the volume percentage of copper powder, nozzle temperature and injection pressure of injection moulding machine were investigated. The analysis was done using Design Expert Software by implementing design of experiment method. From the analysis, the significant effects were determined and mathematical models of only significant effect were established. In order to ensure the validity of the model, confirmation run was done and percentage errors were calculated. It was found that the best combination parameter setting to maximize the value of tensile strength is volume percentage of copper powder of 3.00%, the nozzle temperature of 195oC and the injection pressure of 65%, and the best combination parameter settings to maximize the value of thermal conductivity is volume percentage of copper powder of 7.00%, the nozzle temperature of 195oC and the injection pressure of 65% as recommended

Piezoresistivity and conductance anisotropy of tunneling-percolating systems

Percolating networks based on interparticle tunneling conduction are shown to yield a logarithmic divergent piezoresistive response close to the critical point as long as the electrical conductivity becomes nonuniversal. At the same time, the piezoresistivity or, equivalently, the conductivity anisotropy exponent $\lambda$ remains universal also when the conductive exponent is not, suggesting a purely geometric origin of $\lambda$. We discuss our results in relation to the nature of transport for a variety of materials such as carbon-black--polymer composites and RuO_2-glass systems which show nonuniversal transport properties and coexistence between tunneling and percolating behaviors.Comment: 6 pages, 3 figures, Added discussion on experiment

Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation.

BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules - interleukin-8 and vascular endothelial growth factor. CONCLUSION: Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases

FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.Breast Cancer Research FoundationThis is the final version of the article. It first appeared from Oxford University Press via https://doi.org/10.1093/carcin/bgw06