A Recipe for Success: When Traditional Yogurt meets Marketing & Innovation - Killowen Case Study

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IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251

Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1–mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion–dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1–induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface

Exploring the Use of Immersive Technologies to Enhance the Student Experience

This paper reports on the initial phase of a National Forum funded Learning Enhancement Project (LEP), under the Strategic Alignment of Teaching and Learning Enhancement (SATLE) funding stream. The purpose of the LEP is to explore the use of immersive technologies such as Augmented Reality, Virtual Reality and 360o Learning in three key domain areas within one higher education institution in Ireland. While significant research has been conducted into the use of these technologies in training and business contexts, the application and use in higher education is still scarce. Radianti et al. (2020) suggest that while the use of virtual reality in higher education is promising, it is still quite experimental and focuses more on performance and usability than learning-oriented applications. Augmented Reality has been used in areas such as teacher education (Sáez-López, 2020) and EFL (Arkhipova, 2022) but is also largely experimental. Together with Mixed Reality and 360-degree Learning, these technologies have the potential to offer students a more immersive learning experience. Three domain areas are involved in this project: Online Learning; the university library; and the academic discipline of Business Tourism. It is envisaged that based on their expertise and experience team members will trial at least two of the immersive technologies with their students during the academic year 2023-2024. Engaging the students in the research will foster a partnership approach and provide an understanding of how this new approach to learning benefits the students but will also reveal the challenges associated with introducing new technologies

Ophthalmic outcomes following neonatal hypoxic ischaemic encephalopathy; oculomotor, biometric and refractive data in early childhood

Objectives: To investigate the functional and structural impact of neonatal hypoxic ischaemic encephalopathy (HIE) on childhood visual development. Methods: In a prospective study, the neurocognitive outcomes of 42 children with a history of neonatal HIE were assessed serially up to 5 years. For the ophthalmic component of the study, visual, refractive, orthoptic and ocular biometry measurements were obtained in 32 children, with axial length measurements estimated using the IOLMaster. Results: For the 32 children who completed the ophthalmic component of the study, severity of HIE grade was determined to be mild, moderate, or severe in 18 (56.3%), 13 (40.6%), and 1 (3.1%) cases, respectively. One (3.1%) child was classed as visually impaired. Twelve (37.5%) were found to have ametropia. Mean (±SD) axial length was 22.09 (±0.81) mm, within the normal range for the age of this cohort. Seven of the 42 (16.7%) children who were involved in the larger neurodevelopmental arm of the study had clinical evidence of a squint. There was no correlation between the severity of HIE grade at birth and axial length or occurrence of squint. Conclusions: Neonatal HIE is associated with a higher incidence of squint compared with the general paediatric population. This occurred irrespective of severity of HIE grade. The ocular biometry measurements were consistent with published normative data, and no significant difference in ocular biometry was demonstrated between HIE severity groups

The effect of vitamin K1 supplemention for 12 months on bone mineral density and indices of vitamin K status and bone turnover in adult Crohn s disease patients

peer-reviewedAdult patients with Crohn’s disease (CD), even those in remission, have been shown to have higher circulating under-g-carboxylated osteocalcin (ucOC) concentrations, a sensitive marker of vitamin K nutritional status(1), compared to age- and sex-matched healthy control subjects(2,3). Increased concentrations of ucOC in CD patients in these studies appear to be positively and negatively associated with the rate of bone turnover(3) and bone mineral density (BMD) at some sites(2), respectively. The aim of our study was to investigate whether supplementation with vitamin K1 (1000 mg/d) for 12 months had a positive effect on the rate of bone turnover and BMD in CD patients. We have previously shown that this level of supplementation maximally suppresses the degree of ucOC in CD patients(4).PUBLISHEDpeer-reviewe

Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation

Orally administered β-glucan attenuates the Th2 response in a model of airway hypersensitivity

β-Glucan is a polysaccharide that can be extracted from fungal cell walls. Wellmune WGP®, a preparation of β-1,3/1,6-glucans, is a dietary supplement that has immunomodulating properties. Here we investigated the effect WGP had on a mouse model of asthma. OVA-induced asthma in mice is characterized by infiltration of eosinophils into the lung, production of Th2 cytokines and IgE. Daily oral administration of WGP (400 µg) significantly reduced the influx of eosinophils into the lungs of OVA-challenged mice compared to control mice. In addition, WGP inhibited pulmonary production of Th2 cytokines (IL-4, IL-5, IL-13), however serum IgE levels were unaffected by WGP treatment. These data indicate that WGP could potentially be useful as an oral supplement for some asthma patients, however, it would need to be combined with therapies that target other aspects of the disease such as IgE levels. As such, further studies that examine the potential of WGP in combination with other therapies should be explored

Feasibility study of computational occupational dosimetry: evaluating a proof-of-concept in an endovascular and interventional cardiology setting

Individual monitoring of radiation workers is essential to ensure compliance with legal dose limits and to ensure that doses are As Low As Reasonably Achievable. However, large uncertainties still exist in personal dosimetry and there are issues with compliance and incorrect wearing of dosimeters. The objective of the PODIUM (Personal Online Dosimetry Using Computational Methods) project was to improve personal dosimetry by an innovative approach: the development of an online dosimetry application based on computer simulations without the use of physical dosimeters. Occupational doses were calculated based on the use of camera tracking devices, flexible individualised phantoms and data from the radiation source. When combined with fast Monte Carlo simulation codes, the aim was to perform personal dosimetry in real-time. A key component of the PODIUM project was to assess and validate the methodology in interventional radiology workplaces where improvements in dosimetry are needed. This paper describes the feasibility of implementing the PODIUM approach in a clinical setting. Validation was carried out using dosimeters worn by Vascular Surgeons and Interventional Cardiologists during patient procedures at a hospital in Ireland. Our preliminary results from this feasibility study show acceptable differences of the order of 40% between calculated and measured staff doses, in terms of the personal dose equivalent quantity Hp(10), however there is a greater deviation for more complex cases and improvements are needed. The challenges of using the system in busy interventional rooms have informed the future needs and applicability of PODIUM. The availability of an online personal dosimetry application has the potential to overcome problems that arise from the use of current dosimeters. In addition, it should increase awareness of radiation protection among staff. Some limitations remain and a second phase of development would be required to bring the PODIUM method into operation in a hospital setting. However, an early prototype system has been tested in a clinical setting and the results from this two-year proof-of-concept PODIUM project are very promising for future development.Peer ReviewedPostprint (published version

Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn's disease.

peer-reviewedAlthough epidemiological findings support a role for vitamin K status in the improvement of bone indices in adult patients with Crohn's disease (CD), this needs to be confirmed in double-blind, randomised controlled trials (RCT) with phylloquinone (vitamin K1). By conducting two RCT, the present study aimed to first establish whether supplementation with 1000 μg of phylloquinone daily near-maximally suppresses the percentage of undercarboxylated osteocalcin in serum (%ucOC; marker of vitamin K status) in adult patients with CD currently in remission as it does in healthy adults and second determine the effect of supplementation with phylloquinone at this dose for 12 months on the indices of bone turnover and bone mass. The initial dose-ranging RCT was conducted in adult patients with CD (n 10 per group) using 0 (placebo), 1000 or 2000 μg of phylloquinone daily for 2 weeks. In the main RCT, the effect of placebo v. 1000 μg vitamin K/d (both co-administered with Ca (500 mg/d) and vitamin D3 (10 μg/d)) for 12 months (n 43 per group) on the biochemical indices of bone turnover (determined by enzyme immunoassay) and bone mass (determined by dual-energy X-ray absorptiometry) were investigated. At baseline, the mean %ucOC was 47 %, and this was suppressed upon supplementation with 1000 μg of phylloquinone daily ( - 81 %; P0·1) on bone turnover markers or on the bone mass of the lumbar spine or femur, but modestly increased (P< 0·05) the bone mass of the total radius. Despite near maximal suppression of serum %ucOC, supplementation with 1000 μg of phylloquinone daily (with Ca and vitamin D3) had no effect on the indices of bone health in adult CD patients with likely vitamin K insufficiency.PUBLISHEDpeer-reviewe