Search Results (7)

Adenosine deaminase acting on RNA 1 (ADAR1) is the principal enzyme for the adenosine-to-inosine RNA editing that prevents the aberrant activation of cytosolic nucleic acid sensors by endogenous double stranded RNAs and the activation of interferon-stimulated genes. In mice, the conditional neural crest deletion of Adar1 reduces the survival of melanocytes and alters the differentiation of Schwann cells that fail to myelinate nerve fibers in the peripheral nervous system. These myelination defects are partially rescued upon the concomitant removal of the Mda5 antiviral dsRNA sensor in vitro, suggesting implication of the Mda5/Mavs pathway and downstream effectors in the genesis of Adar1 mutant phenotypes. By analyzing RNA-Seq data from the sciatic nerves of mouse pups after conditional neural crest deletion of Adar1 (Adar1cKO), we here identified the transcription factors deregulated in Adar1cKO mutants compared to the controls. Through Adar1;Mavs and Adar1cKO;Egr1 double-mutant mouse rescue analyses, we then highlighted that the aberrant activation of the Mavs adapter protein and overexpression of the early growth response 1 (EGR1) transcription factor contribute to the Adar1 deletion associated defects in Schwann cell development in vivo. In silico and in vitro gene regulation studies additionally suggested that EGR1 might mediate this inhibitory effect through the aberrant regulation of EGR2-regulated myelin genes. We thus demonstrate the role of the Mda5/Mavs pathway, but also that of the Schwann cell transcription factors in Adar1-associated peripheral myelination defects. Full article

Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1$\mathsf{\alpha }$, IL-22, and TNF-$\mathsf{\beta }$ and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes. Full article

Global Researchers Advancing Catholic Education (G.R.A.C.E) is a unique Community of Practice (CoP). The CoP methodology was applied within G.R.A.C.E for its capacity to connect multi-disciplinary and international academics and practitioners within Catholic Education. This paper presents key insights gathered from the G.R.A.C.E steering committee regarding their perspectives on the journey of initiating this unique CoP. A small qualitative research project framed within a phenomenological interpretivist theoretical perspective was employed to ascertain the participants’ hopes, experiences, impact as well as challenges and opportunities. A Qualtrics questionnaire was the selected data collection method. Findings suggest that the experience of G.R.A.C.E has been a positive one, affirming the CoP methodology adopted was effective in ensuring the hopes that members held for the CoP were actualised. Challenges and opportunities identified in the findings provide insight into the future direction of this truly global initiative. Full article

Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as pivotal in their recruitment to omentum. Here, we elucidate whether exposure to the soluble microenvironment of OAC omentum, and in particular fractalkine and IL-15 affects NK cell homing capacity towards oesophageal tumour. Our data uncover diminished NK cell migration towards OAC tumour tissue conditioned media (TCM) following exposure to omental adipose tissue conditioned media (ACM) and reveal that this migration can be rescued with CX3CR1 antagonist E6130. Furthermore, we show that fractalkine has opposing effects on NK cell migration towards TCM, when used alone or in combination with IL-15 and uncover its inhibitory effects on IL-15-mediated stimulation of death receptor ligand expression. Interestingly, treatment with fractalkine and/or IL-15 do not significantly affect NK cell adhesion to MAdCAM-1, despite changes they elicit to the expression of integrin α4β7. This study provides further evidence that CX3CR1 antagonism has therapeutic utility in rescuing NK cells from the deleterious effects of the omentum and fractalkine in OAC, thus limiting their dysfunction. Full article

This work aimed to (i) determine the reliability of a portable Bluetooth colourimeter for fruit colour measurements; (ii) characterise the changes in quantitative skin colour attributes in a nectarine cultivar in response to time from harvest; and (iii) determine the influence of row orientation and training system on nectarine skin colour. The skin colour attributes measured with the colourimeter, namely L*, a* and b*, were calibrated and validated against a reference spectrophotometer. C* and h° were obtained from a* and b*. Skin colour was measured in situ from 42 days before to 6 days after harvest on ‘Majestic Pearl’ nectarines subjected to different row orientations and training systems. Validation models showed high reliability of colour estimations. The trends of colour attributes over time were characterised by cubic regression models, with h° proving to be the best parameter to describe changes of colour over time, with a clear link to the maturation process. No significant effects of row orientation and training system on skin colour were observed at harvest. Overall, the device proved reliable for fruit colour detection. Results of this study highlight the potential of h° as a quantitative index to monitor ripening prior to harvest in ‘Majestic Pearl’ nectarines. Full article

Gender equity in academia is a long-standing struggle. Although common to all disciplines, the impacts of bias and stereotypes are particularly pronounced in science, technology, engineering and mathematics (STEM) disciplines. This paper explores what barriers exist for the career progression of women in academia in STEM disciplines in order to identify key issues and potential solutions. In particular, we were interested in how women perceive the barriers affecting their careers in comparison to their male colleagues. Fourteen focus groups with female-identifying academics showed that there were core barriers to career progression, which spanned countries, disciplines and career stages. Entrenched biases, stereotypes, double standards, bullying and harassment all negatively impact women’s confidence and sense of belonging. Women also face an additional biological burden, often being pushed to choose between having children or a career. Participants felt that their experiences as STEM academics were noticeably different to those of their male colleagues, where many of the commonly occurring barriers for women were simply non-issues for men. The results of this study indicate that some of these barriers can be overcome through networks, mentoring and allies. Addressing these barriers requires a reshaping of the gendered norms that currently limit progress to equity and inclusion. Full article

Soils from humid forests undergo spatial and temporal variations in moisture and oxygen (O₂) in response to rainfall, and induce changes in iron (Fe) and carbon (C) biogeochemistry. We hypothesized that high rainfall periods stimulate Fe and C cycling, with the greatest effects in areas of high soil moisture. To test this, we measured Fe and C cycling across three catenas at valley, slope, and ridge positions every two days for a two-month period in a rainforest in Puerto Rico. Over 12 days without rain, soil moisture, Fe^II, rapidly reducible Fe oxides (Fe^III_RR), and dissolved organic C (DOC) declined, but Eh and O₂ increased; conversely, during a 10-day period of intense rain (290 mm), we observed the opposite trends. Mixed-effects models suggest precipitation predicted soil moisture, soil redox potential (Eh), and O₂, which in turn influenced Fe reduction/oxidation, C dissolution, and mineralization processes. The approximate turnover time for HCl-extractable Fe^II was four days for both production and consumption, and may be driven by fluctuations in Fe^III_RR, which ranged from 42% to 100% of citrate–ascorbate-extractable Fe^III (short-range order (SRO)-Fe^III) at a given site. Our results demonstrated that periods of high precipitation (hot moments) influenced Fe and C-cycling within day-to-week timescales, and were more pronounced in humid valleys (hot spots). Full article