Myoglobin regulates fatty acid trafficking and lipid metabolism in mammary epithelial cells

Myoglobin (MB) is known to bind and deliver oxygen in striated muscles at high expression levels. MB is also expressed at much reduced levels in mammary epithelial cells, where the protein´s function is unclear. In this study, we aim to determine whether MB impacts fatty acid trafficking and facilitates aerobic fatty acid ß-oxidation in mammary epithelial cells. We utilized MB-wildtype versus MB-knockout mice and human breast cancer cells to examine the impact of MB and its oxygenation status on fatty acid metabolism in mouse milk and mammary epithelia. MB deficient cells were generated through CRISPR/Cas9 and TALEN approaches and exposed to various oxygen tensions. Fatty acid profiling of milk and cell extracts were performed along with cell labelling and immunocytochemistry. Our findings show that MB expression in mammary epithelial cells promoted fatty acid oxidation while reducing stearyl-CoA desaturase activity for lipogenesis. In cells and milk product, presence of oxygenated MB significantly elevated indices of limited fatty acid ß-oxidation, i.e., the organelle-bound removal of a C2 moiety from long-chain saturated or monounsaturated fatty acids, thus shifting the composition toward more saturated and shorter fatty acid species. Presence of the globin also increased cytoplasmic fatty acid solubility under normoxia and fatty acid deposition to lipid droplets under severe hypoxia. We conclude that MB can function in mammary epithelia as intracellular O$_{2}$-dependent shuttle of oxidizable fatty acid substrates. MB’s impact on limited oxidation of fatty acids could generate inflammatory mediator lipokines, such as 7-hexadecenoate. Thus, the novel functions of MB in breast epithelia described herein range from controlling fatty acid turnover and homeostasis to influencing inflammatory signalling cascade. Future work is needed to analyse to what extent these novel roles of MB also apply to myocytic cell physiology and malignant cell behaviour, respectively

'The drug survey app' : a protocol for developing and validating an interactive population survey tool for drug use among Aboriginal and Torres Strait Islander Australians

Background: Disadvantage and transgenerational trauma contribute to Aboriginal and Torres Strait Islander (Indigenous) Australians being more likely to experience adverse health consequences from alcohol and other drug use than non-Indigenous peoples. Addressing these health inequities requires local monitoring of alcohol and other drug use. While culturally appropriate methods for measuring drinking patterns among Indigenous Australians have been established, no similar methods are available for measuring other drug use patterns (amount and frequency of consumption). This paper describes a protocol for creating and validating a tablet-based survey for alcohol and other drugs (“The Drug Survey App”). Methods: The Drug Survey App will be co-designed with stakeholders including Indigenous Australian health professionals, addiction specialists, community leaders, and researchers. The App will allow participants to describe their drug use fexibly with an interactive, visual interface. The validity of estimated consumption patterns, and risk assessments will be tested against those made in clinical interviews conducted by Indigenous Australian health professionals. We will then trial the App as a population survey tool by using the App to determine the prevalence of substance use in two Indigenous communities. Discussion: The App could empower Indigenous Australian communities to conduct independent research that informs local prevention and treatment efforts

Математичні основи визначення функціонального стану операторів складних технологічних об’єктів

Забезпечення високої надійності роботи оператора, а, відповідно, системи «людина – машина» (СЛМ), – є пріоритетним завданням для більшості сфер промисловості та сучасного виробництва. Тому важливим є розробка заходів по підвищенню кваліфікації операторів складних технологічних об’єктів (СТО), шляхом підбору математичного апарату для який б дав можливість підвищити надійність його діяльності в структурі СЛМ

M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice

In T-cell–dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell–like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell–dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive

Sustained Platelet-Derived Growth Factor Receptor α Signaling in Osteoblasts Results in Craniosynostosis by Overactivating the Phospholipase C-γ Pathway▿ †

The development and growth of the skull is controlled by cranial sutures, which serve as growth centers for osteogenesis by providing a pool of osteoprogenitors. These osteoprogenitors undergo intramembranous ossification by direct differentiation into osteoblasts, which synthesize the components of the extracellular bone matrix. A dysregulation of osteoblast differentiation can lead to premature fusion of sutures, resulting in an abnormal skull shape, a disease called craniosynostosis. Although several genes could be linked to craniosynostosis, the mechanisms regulating cranial suture development remain largely elusive. We have established transgenic mice conditionally expressing an autoactivated platelet-derived growth factor receptor α (PDGFRα) in neural crest cells (NCCs) and their derivatives. In these mice, premature fusion of NCC-derived sutures occurred at early postnatal stages. In vivo and in vitro experiments demonstrated enhanced proliferation of osteoprogenitors and accelerated ossification of osteoblasts. Furthermore, in osteoblasts expressing the autoactivated receptor, we detected an upregulation of the phospholipase C-γ (PLC-γ) pathway. Treatment of differentiating osteoblasts with a PLC-γ-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRα signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-γ pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis