Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

BACKGROUND: The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. METHODS: Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. RESULTS: Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. CONCLUSIONS: These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression.

Ribosomal frameshifting and transcriptional slippage: from genetic steganography and cryptography to adventitious use

Genetic decoding is not ‘frozen’ as was earlier thought, but dynamic. One facet of this is frameshifting that often results in synthesis of a C-terminal region encoded by a new frame. Ribosomal frameshifting is utilized for the synthesis of additional products, for regulatory purposes and for translational ‘correction’ of problem or ‘savior’ indels. Utilization for synthesis of additional products occurs prominently in the decoding of mobile chromosomal element and viral genomes. One class of regulatory frameshifting of stable chromosomal genes governs cellular polyamine levels from yeasts to humans. In many cases of productively utilized frameshifting, the proportion of ribosomes that frameshift at a shift-prone site is enhanced by specific nascent peptide or mRNA context features. Such mRNA signals, which can be 5′ or 3′ of the shift site or both, can act by pairing with ribosomal RNA or as stem loops or pseudoknots even with one component being 4 kb 3′ from the shift site. Transcriptional realignment at slippage-prone sequences also generates productively utilized products encoded trans-frame with respect to the genomic sequence. This too can be enhanced by nucleic acid structure. Together with dynamic codon redefinition, frameshifting is one of the forms of recoding that enriches gene expression.

Spatial overlap of grey seals and fisheries in Irish waters, some new insights using telemetry technology and VMS

Seals and humans often target the same food resource, leading to competition. This is of mounting concern with fish stocks in global decline. Grey seals were tracked from southeast Ireland, an area of mixed demersal and pelagic fisheries, and overlap with fisheries on the Celtic Shelf and Irish Sea was assessed. Overall, there was low overlap between the tagged seals and fisheries. However, when we separate active (e.g. trawls) and passive gear (e.g. nets, lines) fisheries, a different picture emerged. Overlap with active fisheries was no different from that expected under a random distribution, but overlap with passive fisheries was significantly higher. This suggests that grey seals may be targeting the same areas as passive fisheries and/or specifically targeting passive gear. There was variation in foraging areas between individual seals suggesting habitat partitioning to reduce intra-specific competition or potential individual specialisation in foraging behaviour. Our findings support other recent assertions that seal/fisheries interactions in Irish waters are an issue in inshore passive fisheries, most likely at the operational and individual level. This suggests that seal population management measures would be unjustifiable, and mitigation is best focused on minimizing interactions at nets.

Obesity, diet quality and absenteeism in a working population

The relationship between workplace absenteeism and adverse lifestyle factors (smoking, physical inactivity and poor dietary patterns) remains ambiguous. Reliance on self-reported absenteeism and obesity measures may contribute to this uncertainty. Using objective absenteeism and health status measures, the present study aimed to investigate what health status outcomes and lifestyle factors influence workplace absenteeism. Cross-sectional data were obtained from a complex workplace dietary intervention trial, the Food Choice at Work Study. Four multinational manufacturing workplaces in Cork, Republic of Ireland. Participants included 540 randomly selected employees from the four workplaces. Annual count absenteeism data were collected. Physical assessments included objective health status measures (BMI, midway waist circumference and blood pressure). FFQ measured diet quality from which DASH (Dietary Approaches to Stop Hypertension) scores were constructed. A zero-inflated negative binomial (zinb) regression model examined associations between health status outcomes, lifestyle characteristics and absenteeism. The mean number of absences was 2·5 (sd 4·5) d. After controlling for sociodemographic and lifestyle characteristics, the zinb model indicated that absenteeism was positively associated with central obesity, increasing expected absence rate by 72 %. Consuming a high-quality diet and engaging in moderate levels of physical activity were negatively associated with absenteeism and reduced expected frequency by 50 % and 36 %, respectively. Being in a managerial/supervisory position also reduced expected frequency by 50 %. To reduce absenteeism, workplace health promotion policies should incorporate recommendations designed to prevent and manage excess weight, improve diet quality and increase physical activity levels of employees.

CpxR activates MexAB-OprM efflux pump expression and enhances antibiotic resistance in both laboratory and clinical nalB-type isolates of Pseudomonas aeruginosa

Resistance-Nodulation-Division (RND) efflux pumps are responsible for multidrug resistance in Pseudomonas aeruginosa. In this study, we demonstrate that CpxR, previously identified as a regulator of the cell envelope stress response in Escherichia coli, is directly involved in activation of expression of RND efflux pump MexAB-OprM in P. aeruginosa. A conserved CpxR binding site was identified upstream of the mexA promoter in all genome-sequenced P. aeruginosa strains. CpxR is required to enhance mexAB-oprM expression and drug resistance, in the absence of repressor MexR, in P. aeruginosa strains PA14. As defective mexR is a genetic trait associated with the clinical emergence of nalB-type multidrug resistance in P. aeruginosa during antibiotic treatment, we investigated the involvement of CpxR in regulating multidrug resistance among resistant isolates generated in the laboratory via antibiotic treatment and collected in clinical settings. CpxR is required to activate expression of mexAB-oprM and enhances drug resistance, in the absence or presence of MexR, in ofloxacin-cefsulodin-resistant isolates generated in the laboratory. Furthermore, CpxR was also important in the mexR-defective clinical isolates. The newly identified regulatory linkage between CpxR and the MexAB-OprM efflux pump highlights the presence of a complex regulatory network modulating multidrug resistance in P. aeruginosa.

Youth-Physical Activity Towards Health: evidence and background to the development of the Y-PATH physical activity intervention for adolescents

Background: Despite known benefits of regular physical activity for health and well-being, many studies suggest that levels of physical activity in young people are low, and decline dramatically during adolescence. The purpose of the current research was to gather data on adolescent youth in order to inform the development of a targeted physical activity intervention. Methods: Cross-sectional data on physical activity levels (using self report and accelerometry), psychological correlates of physical activity, anthropometic characteristics, and the fundamental movement skill proficiency of 256 youth (53% male, 12.40 ± 0.51 years) were collected. A subsample (n = 59) participated in focus group interviews to explore their perceptions of health and identify barriers and motivators to participation in physical activity. Results: Findings indicate that the majority of youth (67%) were not accumulating the minimum 60 minutes of physical activity recommended daily for health, and that 99.5% did not achieve the fundamental movement skill proficiency expected for their age. Body mass index data showed that 25% of youth were classified as overweight or obese. Self-efficacy and physical activity attitude scores were significantly different (p < 0.05) between low, moderate and high active participants. Active and inactive youth reported differences in their perceived understanding of health and their barriers to physical activity participation, with active youth relating nutrition, exercise, energy and sports with the definition of ‘being healthy’, and inactive youth attributing primarily nutritional concepts to ‘being healthy’. Conclusions: Data show a need for targeting low levels of physical activity in youth through addressing poor health related activity knowledge and low fundamental movement skill proficiency. The Y-PATH intervention was developed in accordance with the present study findings; details of the intervention format are presented.

Autoinducer-2 plays a crucial role in gut colonization and probiotic functionality of Bifidobacterium breve UCC2003

In the present study we show that luxS of Bifidobacterium breve UCC2003 is involved in the production of the interspecies signaling molecule autoinducer-2 (AI-2), and that this gene is essential for gastrointestinal colonization of a murine host, while it is also involved in providing protection against Salmonella infection in Caenorhabditis elegans. We demonstrate that a B. breve luxS-insertion mutant is significantly more susceptible to iron chelators than the WT strain and that this sensitivity can be partially reverted in the presence of the AI-2 precursor DPD. Furthermore, we show that several genes of an iron starvation-induced gene cluster, which are downregulated in the luxS-insertion mutant and which encodes a presumed iron-uptake system, are transcriptionally upregulated under in vivo conditions. Mutation of two genes of this cluster in B. breve UCC2003 renders the derived mutant strains sensitive to iron chelators while deficient in their ability to confer gut pathogen protection to Salmonella-infected nematodes. Since a functional luxS gene is present in all tested members of the genus Bifidobacterium, we conclude that bifidobacteria operate a LuxS-mediated system for gut colonization and pathogen protection that is correlated with iron acquisition.

Variations between post- and pre-harvest seasons in stunting, wasting, and Infant and Young Child Feeding (IYCF) practices among children 6-23 months of age in lowland and midland agro-ecological zones of rural Ethiopia

Introduction: Food availability and access are strongly affected by seasonality in Ethiopia. However, there are little data on seasonal variation in Infant and Young Child Feeding (IYCF) practices and malnutrition among 6-23 months old children in different agro-ecological zones of rural Ethiopia. Methods: Socio-demographic, anthropometry and IYCF indicators were assessed in post- and pre-harvest seasons among children aged 6–23 months of age randomly selected from rural villages of lowland and midland agro-ecological zones. Results: Child stunting and underweight increased from prevalence of 39.8% and 26.9% in post-harvest to 46.0% and 31.8% in pre-harvest seasons, respectively. The biggest increase in prevalence of stunting and underweight between post- and pre-harvest seasons was noted in the midland zone. Wasting decreased from 11.6% post-harvest to 8.5% pre-harvest, with the biggest decline recorded in the lowland zone. Minimum meal frequency, minimum acceptable diet and poor dietary diversity increased considerably in pre-harvest compared to post-harvest season in the lowland zone. Feeding practices and maternal age were predictors of wasting, while women’s dietary diversity and children age was predictor of child dietary diversity in both seasons. Conclusion: There is seasonal variation in malnutrition and IYCF practices among children 6-23 months of age with more pronounced effect in midland agro-ecological zone. A major contributing factor for child malnutrition may be poor feeding practices. Health information strategies focused on both IYCF practices and dietary diversity of mothers could be a sensible approach to reduce the burden of child malnutrition in rural Ethiopia.

Progesterone attenuates microglial-driven retinal degeneration and stimulates protective Fractalkine-CX3CR1 signaling

Retinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics. In 2011, our group first demonstrated that the synthetic progesterone analogue ‘Norgestrel’ is neuroprotective in two mouse models of retinal degeneration, including the rd10 mouse. We have since elucidated several mechanisms by which Norgestrel protects stressed photoreceptors, such as upregulating growth factors. This study consequently aimed to further characterize Norgestrel’s neuroprotective effects. Specifically, we sought to investigate the role that microglia might play; for microglial-derived inflammation has been shown to potentiate neurodegeneration. Dams of post-natal day (P) 10 rd10 pups were given a Norgestrel-supplemented diet (80mg/kg). Upon weaning, pups remained on Norgestrel. Tissue was harvested from P15-P50 rd10 mice on control or Norgestrel-supplemented diet. Norgestrel-diet administration provided significant retinal protection out to P40 in rd10 mice. Alterations in microglial activity coincided with significant protection, implicating microglial changes in Norgestrel-induced neuroprotection. Utilizing primary cultures of retinal microglia and 661W photoreceptor-like cells, we show that rd10 microglia drive neuronal cell death. We reveal a novel role of Norgestrel, acting directly on microglia to reduce pro-inflammatory activation and prevent neuronal cell death. Norgestrel effectively suppresses cytokine, chemokine and danger-associated molecular pattern molecule (DAMP) expression in the rd10 retina. Remarkably, Norgestrel upregulates fractalkine-CX3CR1 signaling 1 000-fold at the RNA level, in the rd10 mouse. Fractalkine-CX3CR1 signaling has been shown to protect neurons by regulating retinal microglial activation and migration. Ultimately, these results present Norgestrel as a promising treatment for RP, with dual actions as a neuroprotective and anti-inflammatory agent in the retina.

Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior

There is a growing recognition of the importance of the commensal intestinal microbiota in the development and later function of the central nervous system. Research using germ-free mice (mice raised without any exposure to microorganisms) has provided some of the most persuasive evidence for a role of these bacteria in gut-brain signalling. Key findings show that the microbiota is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition. Furthermore, the microbiota maintains central nervous system homeostasis by regulating immune function and blood brain barrier integrity. Studies have also found that the gut microbiota influences neurotransmitter, synaptic, and neurotrophic signalling systems and neurogenesis. The principle advantage of the germ-free mouse model is in proof-of-principle studies and that a complete microbiota or defined consortiums of bacteria can be introduced at various developmental time points. However, a germ-free upbringing can induce permanent neurodevelopmental deficits that may deem the model unsuitable for specific scientific queries that do not involve early-life microbial deficiency. As such, alternatives and complementary strategies to the germ-free model are warranted and include antibiotic treatment to create microbiota-deficient animals at distinct time points across the lifespan. Increasing our understanding of the impact of the gut microbiota on brain and behavior has the potential to inform novel management strategies for stress-related gastrointestinal and neuropsychiatric disorders.

Patterns of psychotropic prescribing and polypharmacy in older hospitalized patients in Ireland: the influence of dementia on prescribing

Neuropsychiatric Symptoms (NPS) are ubiquitous in dementia and are often treated pharmacologically. The objectives of this study were to describe the use of psychotropic, anti-cholinergic, and deliriogenic medications and to identify the prevalence of polypharmacy and psychotropic polypharmacy, among older hospitalized patients in Ireland, with and without dementia. All older patients (≥ 70 years old) that had elective or emergency admissions to six Irish study hospitals were eligible for inclusion in a longitudinal observational study. Of 676 eligible patients, 598 patients were recruited and diagnosed as having dementia, or not, by medical experts. These 598 patients were assessed for delirium, medication use, co-morbidity, functional ability, and nutritional status. We conducted a retrospective cross-sectional analysis of medication data on admission for 583/598 patients with complete medication data, and controlled for age, sex, and co-morbidity. Of 149 patients diagnosed with dementia, only 53 had a previous diagnosis. At hospital admission, 458/583 patients experienced polypharmacy (≥ 5 medications). People with dementia (PwD) were significantly more likely to be prescribed at least one psychotropic medication than patients without dementia (99/147 vs. 182/436; p < 0.001). PwD were also more likely to experience psychotropic polypharmacy (≥ two psychotropics) than those without dementia (54/147 vs. 61/436; p < 0.001). There were no significant differences in the prescribing patterns of anti-cholinergics (23/147 vs. 42/436; p = 0.18) or deliriogenics (79/147 vs. 235/436; p = 0.62). Polypharmacy and psychotropic drug use is highly prevalent in older Irish hospitalized patients, especially in PwD. Hospital admission presents an ideal time for medication reviews in PwD.

Alcohol consumption among university students in Ireland and the United Kingdom from 2002 to 2014: a systematic review

Background: Alcohol is a leading cause of global suffering. Europe reports the uppermost volume of alcohol consumption in the world, with Ireland and the United Kingdom reporting the highest levels of binge drinking and drunkenness. Levels of consumption are elevated among university students. Thus, this literature review aims to summarise the current research on alcohol consumption among university students in the Republic of Ireland and the United Kingdom. Methods: MEDLINE, CINAHL, EMBASE and PsychInfo were systematically searched for literature from January 2002 until December 2014. Each database was searched using the following search pillars: alcohol, university student, Ireland or the United Kingdom and prevalence studies. Results: Two thousand one hundred twenty eight articles were retrieved from electronic database searching. These were title searched for relevance. 113 full texts were retrieved and assessed for eligibility. Of these, 29 articles were deemed to meet inclusion criteria for the review. Almost two thirds of students reported a hazardous alcohol consumption score on the AUDIT scale. Over 20 % reported alcohol problems over their lifetime using CAGE while over 20 % exceed sensible limits each week. Noteworthy is the narrowing of the gender gap throughout the past decade. Conclusion: This is the first review to investigate consumption patterns of university students in Ireland and the United Kingdom. A range of sampling strategies and screening tools are employed in alcohol research which preclude comparability. The current review provides an overview of consumption patterns to guide policy development.

Evaluation of physicochemical and glycaemic properties of commercial plant-based milk substitutes

The market for plant-based dairy-type products is growing as consumers replace bovine milk in their diet, for medical reasons or as a lifestyle choice. A screening of 17 different commercial plant-based milk substitutes based on different cereals, nuts and legumes was performed, including the evaluation of physicochemical and glycaemic properties. Half of the analysed samples had low or no protein contents (<0.5 %). Only samples based on soya showed considerable high protein contents, matching the value of cow’s milk (3.7 %). An in-vitro method was used to predict the glycaemic index. In general, the glycaemic index values ranged from 47 for bovine milk to 64 (almond-based) and up to 100 for rice-based samples. Most of the plant-based milk substitutes were highly unstable with separation rates up to 54.39 %/h. This study demonstrated that nutritional and physicochemical properties of plant-based milk substitutes are strongly dependent on the plant source, processing and fortification. Most products showed low nutritional qualities. Therefore, consumer awareness is important when plant-based milk substitutes are used as an alternative to cow’s milk in the diet.

Cavity ring‑up spectroscopy for dissipative and dispersive sensing in a whispering gallery mode resonator

In whispering gallery mode resonator sensing applications, the conventional way to detect a change in the parameter to be measured is by observing the steady-state transmission spectrum through the coupling waveguide. Alternatively, sensing based on cavity ring-up spectroscopy, i.e. CRUS, can be achieved transiently. In this work, we investigate CRUS using coupled mode equations and find analytical solutions with a large spectral broadening approximation of the input pulse. The relationships between the frequency detuning, coupling gap and ring-up peak height are determined and experimentally verified using an ultrahigh Q-factor silica microsphere. This work shows that distinctive dispersive and dissipative transient sensing can be realised by simply measuring the peak height of the CRUS signal, which may improve the data collection rate.