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The non-antibacterial mechanism of action of azithromycin and other macrolides in respiratory epithelium
(University of Iceland, School of Health Sciences, Faculty of Medicine, 2026-06) Asbjarnarson , Arni; Þórarinn Guðjónsson; Faculty of Medicine (UI); Læknadeild (HÍ); School of Health Sciences (UI); Heilbrigðisvísindasvið (HÍ)
Epithelial barrier failure is a common denominator in multiple acute and chronic respiratory diseases. The respiratory epithelial barrier presents the first line of defence against infectious agents and other particulate matter; continuous exposure of epithelial cells results in molecular and phenotypic changes that evoke conditions such as inflammation, fibrosis, and epithelial-to-mesenchymal transition (EMT). Macrolide antibiotics are known for their off-label use in treatments of chronic respiratory diseases (CRD), primarily due to their anti-inflammatory and immunomodulatory effects. Azithromycin (AZM), in particular, has been recognized for its use in decreasing the frequency of CRD exacerbations. Our research group has previously shown that AZM maintains bronchial epithelial integrity in air-liquid interface (ALI) cell culture conditions. However, the mechanisms underlying this effect are not completely known. The aim of this thesis is to understand the non-antibiotic mechanism of action of macrolides, particularly AZM, in modulation of barrier integrity and metabolism of bronchial epithelial cells. In paper I, the effects of different macrolides (AZM, clarithromycin, erythromycin, roxithromycin and solithromycin) on gene expression and epithelial integrity in ALI culture were compared. AZM treatment, when compared to other macrolides, drastically enhanced barrier integrity, induced phospholipid retention and vesicle build-up. Analysis of gene sequencing data sets revealed AZM treatment distinctly enriched several gene sets, most notably increasing the expression of genes related to keratinocyte differentiation, establishment of skin barrier and downregulation of EMT pathways. The focus of Paper II was the potential role of AZM in EMT. AZM inhibited TGF-β1-induced upregulation of SNAI1, N-cadherin and vimentin, key features of EMT. Furthermore, AZM reduced the expression of caveolin-1 that has previously been linked to EMT. The data presented in Paper II report a potential mechanism by which AZM inhibits EMT via depletion of caveolin-1 and cholesterol from the cell membrane through their transport to a perinuclear location. The aim of Paper III was to expand on and compare the effects of the same macrolide antibiotics as those examined in Paper I, but with a focus on oxidative phosphorylation and mitochondrial function. Macrolide treatment indirectly decreased mitochondrial respiration and lowered protein levels of electron transport chain proteins. However, only AZM treatment caused an increase in reactive oxygen species at 72 hours post treatment along with a downstream increase in lipid peroxidation. The antioxidant pathway of KEAP1/NRF2 was activated and gene expression data from longer treatments (14 and 21 days) in ALI culture revealed that AZM initiated mitochondrial dynamic and protective pathways through mitohormesis. In Paper IV, AZM was compared to a nonantibacterial derivative of AZM (EP395) to determine whether the effects of AZM are distinct from its antimicrobial activity. It was shown that EP395 retained the barrier integrity enhancing capabilities of AZM along with positive enrichment of the same gene sets found to be uniquely affected by AZM treatment, indicating that these effects are distinct from the antibacterial activity. Papers V and VI focused on ventilatorinduced lung injury (VILI) in a rodent model where it was investigated whether macrolides ameliorate the negative effects caused by mechanical ventilation. It was shown that barrier failure correlated with increased expression of the pro-inflammatory cytokine IL-6 and higher tidal volumes. Furthermore, increased oxidative stress and phenotypic changes in mitochondria were observed. Finally, we reported that AZM and EP317, another derivative of AZM with reduced antibacterial activity, ameliorated pulmonary oedema, enhanced barrier integrity, and attenuated inflammatory responses caused by ventilation. Collectively, I have shown that AZM has greater effects on bronchial epithelial barrier integrity than other macrolides, that it inhibits EMT and fortifies mitochondrial resilience. I propose possible mechanistic pathways involved in the beneficial effects of AZM treatment, while recognising that additional research is needed to fully uncover AZM’s involvement in the discussed pathways.
Verk
BDPA radicals for DNP-NMR and a new method for RNA spin-labeling
(University of Iceland, School of Engineering and Natural Sciences, Faculty of Physical Sciences, 2026-06-16) Ahmad, Iram; Snorri Þór Sigurðsson; Faculty of Physical Sciences (UI); Raunvísindadeild (HÍ); School of Engineering and Natural Sciences (UI); Verkfræði- og náttúruvísindasvið (HÍ)
Dynamic nuclear polarization (DNP) is a powerful approach for overcoming the low sensitivity of nuclear magnetic resonance (NMR) spectroscopy and has extensive applications in the study of both materials and biological systems. Electron paramagnetic resonance (EPR) and fluorescence spectroscopy are highly important complementary techniques and are particularly valuable for studying nucleic acid structure and dynamics. The broader application of these methods, however, depends on the availability of suitable polarizing agents and site-specific spectroscopic probes, respectively. This thesis focuses on the development of 1,3 bisdiphenylene-2-phenylallyl (BDPA)-based polarizing agents for DNP-NMR and a facile spin labeling strategy for nucleic acids. The first part describes the development of tailored BDPA derivatives for high-field DNPNMR. The synthesis of the key precursor, tetrabromo BDPA, was first optimized. A tetraazide-BDPA building block was subsequently prepared, enabling conjugation to a variety of alkynes via copper-catalyzed azide-alkyne cycloaddition. Using this strategy, four BDPA derivatives with varied polarity, size, and steric shielding were prepared. Of these, a BDPA-dendrimer derivative exhibited enhanced persistence and superior DNP performance, achieving the highest liquid-state DNP enhancement reported to date in viscous solutions. The second part describes a noncovalent RNA spin labeling strategy based on helical stacking of small RNA hairpins, containing the rigid spin label Çm, on RNA duplexes. Complementary overhangs promoted efficient hairpin-duplex stacking, monitored by EPR spectroscopy. In addition, collaborative projects involving incorporation of rigid and semirigid spin labels and fluorophores in nucleic acids to study their structure, dynamics and interactions with proteins using EPR and fluorescence spectroscopies, are recounted.
Verk
Development of AsymPol- and bTurea-Derived Bis-Nitroxides for DNP-Enhanced NMR in Biological Systems
(University of Iceland, School of Engineering and Natural Sciences, Faculty of Physical Sciences, 2026-06-16) Wilson, Ancy Trisha; Snorri Þór Sigurðsson; Faculty of Physical Sciences (UI); Raunvísindadeild (HÍ); School of Engineering and Natural Sciences (UI); Verkfræði- og náttúruvísindasvið (HÍ)
Dynamic nuclear polarization (DNP)-enhanced solid-state nuclear magnetic resonance (NMR) spectroscopy has emerged as a powerful technique to unravel complex biomolecular structures at atomistic resolution. DNP serves to overcome the inherent insensitivity of NMR by the polarization transfer from unpaired electrons to nuclei of interest under microwave irradiation. The sensitivity gain conferred by DNP enables the detection of biomolecules at their physiological concentration. Nitroxide biradicals have shown to be excellent polarizing agents at 9.4 T and 14.1 T, prompting our interest in utilizing them to investigate complex systems via DNP-NMR. However, their broader applicability is limited by several factors, including synthetic challenges, lack of specificity, poor aqueous solubility, and rapid reduction in a reducing environment. This thesis describes the development of synthetic strategies for nitroxide-based biradicals to address these limitations. Firstly, a series of AsymPol-derivatives, including an isothiocyanate, a tetrazine, a maleimide, a cholesterolbased tripod, and an azide, was synthesized to enable targeting of diverse systems ranging from biomolecules to materials. These radicals enabled targeted DNP, which allows selective enhancement of signals from specific sites. Secondly, bTurea-derived bcTCOOKs and bcTmols were developed as readily accessible and water-soluble derivatives to address synthetic limitations associated with highly performing bis-nitroxide biradicals. Among these, bcTCOOK-M2 was the highest yielding and exhibited particularly high DNP sensitivity. Finally, a synthetic strategy was established for highly water-soluble, reductionresistant nitroxide radicals (43 and 44) for in-cell DNP applications. Their stability in the presence of ascorbic acid was evaluated and compared with known radicals; however, they did not exhibit sufficient stability under reductive conditions.
Verk
An infant diet score, BMI and asthma medication in childhood; Population-based evidence from the Icelandic Maternal and Child Health Study (ICE-MCH).
(University of Iceland, School of Health Sciences, Faculty of Food Science and Nutrition, 2026-06) Jonsdottir, Jenny; Birna Þórisdóttir og Inga Þórsdóttir; Faculty of Food Science and Nutrition (UI); Matvæla- og næringarfræðideild (HÍ); School of Health Sciences (UI); Heilbrigðisvísindasvið (HÍ)
Background and aim: Infant nutrition is a key determinant of both short- and long-term health. However, few population-based studies have integrated information on breastfeeding and complementary feeding into a comprehensive measure and examined its associations with childhood health outcomes. The aim of this doctoral thesis, “An Infant Diet Score, BMI, and Asthma Medication in Childhood: PopulationBased Evidence from the Icelandic Maternal and Child Health Study (ICE-MCH)”, was to investigate associations between infant nutrition, childhood BMI, and pediatric asthma medication use. Materials and methods: The ICE-MCH study includes data from electronic health registers for children born in Iceland between 2009 and 2015, forming a nationwide population-based cohort (N=30,623). Paper I of the thesis describes infant nutrition from a few weeks after birth until one year of age. Nutritional variables were obtained from records completed by primary healthcare nurses during nine routine visits with the infant and their caregiver, most often the mother. A composite measure of infant nutrition quality, the Infant Diet Score (IDS), was derived from these data, based on Icelandic infant feeding recommendations and existing infant diet scores. The IDS comprised six components: duration of exclusive and any breastfeeding, age at introduction of cow’s milk and complementary foods, an estimate of dietary variety, and use of vitamin D supplementation. Higher scores indicated greater adherence to infant nutrition guidelines. Associations between the IDS and growth outcomes were examined, with a focus on the international BMI-for-age z-scores during infancy and toddlerhood (12 and 18 months; Paper I) and childhood (2.5, 4, 6, and 9 years; Paper II). Associations between the IDS and asthma medication between ages 1 and 7 years were investigated using data from the Icelandic Prescription Medicines Register. The outcome was defined as two or more dispensations of asthma medication within a 12- month period (Paper III). In addition to descriptive analyses, linear and logistic regression models were applied, both unadjusted and adjusted for potential confounders. Results: Due to its composite nature, the IDS was calculated for the subset of children with complete nutritional data across all nine visits from 0 to 12 months of age (n = 12,848). Findings from Papers I–III showed that greater adherence to infant nutrition guidelines, reflected by a higher IDS, was associated with more favorable BMI trajectories up to 9 years of age and a lower risk of asthma medication use up to age 7. Children in the lowest IDS quintiles had higher odds of overweight and obesity (based on international definitions) at 12 and 18 months and at 6 and 9 years compared with those in the highest quintile, after adjustment for relevant maternal and birth characteristics. When examining individual components of the score, most consistently shorter duration of exclusive and any breastfeeding were associated with less favorable growth outcomes. Shorter duration of exclusive and any breastfeeding, lower use of vitamin D supplementation, and lower overall IDS were consistently associated with increased odds of having two or more asthma medication dispensations within a 12- month period between ages 1 and 7 years. Conclusions: This study demonstrates that the Infant Diet Score, a composite measure capturing overall diet quality during the first year of life, is a valuable population-based indicator of infant nutrition that can be applied in research on health outcomes. Lower adherence to infant nutrition guidelines in the first year of life is associated with less favorable growth trajectories and increased asthma medication dispensation in childhood. These findings suggest that infant nutrition is an early-life exposure that is important for subsequent child health.
Verk
Réttindi og þátttaka barna : Samstarfsverkefni í leikskólum, á yngsta stigi grunnskóla og á frístundaheimilum Hafnarfjarðarbæjar
(RannUng, 2026-06-09) Hreinsdóttir, Anna Magnea; Björnsdóttir, Margrét Sigríður; Ólafsdóttir, Sara Margrét; Deild kennslu- og menntunarfræði
Skýrslan fjallar um samstarfsverkefnið Réttindi og þátttaka barna sem RannUng og Mennta- og lýðheilsusvið Hafnarfjarðarbæjar unnu með leikskólum, yngsta stigi grunnskóla og frístundaheimilum á árunum 2023–2026. Markmið verkefnisins var að innleiða Barnasáttmála Sameinuðu þjóðanna markvisst í daglegt starf, efla þekkingu starfsfólks, barna og foreldra á réttindum barna og skapa aðstæður þar sem börn geta haft raunveruleg áhrif á eigið skóla- og frístundalíf. Verkefnið byggði á starfendarannsóknum, fræðslu, sameiginlegum fundum, rýnihópaviðtölum og þróun verkefna á hverri starfsstöð, meðal annars um lýðræði í hópastarfi, áhugasviðsval, bókasafn, matartíma og valkerfi í frístund. Niðurstöður sýna að þekking starfsfólks á réttindum barna jókst og varð víða samofin daglegum starfsháttum. Viðhorf til barna þróuðust frá því að líta á þau sem þátttakendur innan fyrirfram ákveðins ramma yfir í að viðurkenna þau sem virka gerendur með eigin sjónarmið og áhrif. Dæmin sýna að þátttaka verður merkingarbær þegar hugmyndir barna eru teknar áfram og leiða til sýnilegra breytinga. Helstu áskoranir tengdust tíma, mannafla, forföllum, ólíkum þörfum barna og togstreitu milli verndar og sjálfræðis. Verkefnið sýnir að innleiðing Barnasáttmálans krefst ígrundunar, skýrrar ábyrgðar, stuðnings stjórnenda og þess að réttindi barna verði hluti af starfsmenningu en ekki viðbótarverkefni. Það veitir jafnframt öðrum starfsstöðvum gagnlegan vegvísi til sambærilegrar þróunar og innleiðingar.

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