Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.

LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson's disease.

Epigenetic modifications in neurodegenerative disease are under investigation for their roles in disease progression. Alterations in acetylation rates of certain Parkinson's disease (PD)-linked genes have been associated with the pathological progression of this disorder. In light of this, and given the lack of disease-modifying therapies for PD, HDAC inhibitors (HDIs) are under consideration as potential pharmacological agents. The neuroprotective effects of pan-HDACs and some class-specific inhibitors have been tested in in vivo and in vitro models of PD, with varying outcomes. Here we used gene co-expression analysis to identify HDACs that are associated with human dopaminergic (DA) neuron development. We identified HDAC3, HDAC5, HDAC6 and HDAC9 as being highly correlated with the DA markers, SLC6A3 and NR4A2. RT-qPCR revealed that mRNA expression of these HDACs exhibited similar temporal profiles during embryonic mouse midbrain DA (mDA) neuron development. We tested the neuroprotective potential of a number of class-specific small molecule HDIs on human SH-SY5Y cells, using neurite growth as a phenotypic readout of neurotrophic action. Neither the class I-specific HDIs, RGFP109 and RGFP966, nor the HDAC6 inhibitor ACY1215, had significant effects on neurite outgrowth. However, the class IIa HDI, LMK235 (a HDAC4/5 inhibitor), significantly increased histone acetylation and neurite outgrowth. We found that LMK235 increased BMP-Smad-dependent transcription in SH-SY5Y cells and that this was required for its neurite growth-promoting effects on SH-SY5Y cells and on DA neurons in primary cultures of embryonic day (E) 14 rat ventral mesencephalon (VM). These effects were also seen in SH-SY5Y cells transfected with HDAC5 siRNA. Furthermore, LMK235 treatment exerted neuroprotective effects against degeneration induced by the DA neurotoxin 1-methyl-4-phenylpyridinium (MPP+), in both SH-SY5Y cells and cultured DA neurons. Treatment with LMK235 was also neuroprotective against axonal degeneration induced by overexpression of wild-type (WT) or A53T mutant α-synuclein in both SH-SY5Y cells and primary cultures of DA neurons. In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD.

On the solvation of the phosphocholine headgroup in an aqueous propylene glycol solution.

The atomic-scale structure of the phosphocholine (PC) headgroup in 30 mol. % propylene glycol (PG) in an aqueous solution has been investigated using a combination of neutron diffraction with isotopic substitution experiments and computer simulation techniques-molecular dynamics and empirical potential structure refinement. Here, the hydration of the PC headgroup remains largely intact compared with the hydration of this group in a bilayer and in a bulk water solution, with the PG molecules showing limited interactions with the headgroup. When direct PG interactions with PC do occur, they are most likely to coordinate to the N(CH3)3+ motifs. Further, PG does not affect the bulk water structure and the addition of PC does not perturb the PG-solvent interactions. This suggests that the reason why PG is able to penetrate into membranes easily is that it does not form strong-hydrogen bonding or electrostatic interactions with the headgroup allowing it to easily move across the membrane barrier.

On the structure of an aqueous propylene glycol solution.

Using a combination of neutron diffraction and empirical potential structure refinement computational modelling, the interactions in a 30 mol. % aqueous solution of propylene glycol (PG), which govern both the hydration and association of this molecule in solution, have been assessed. From this work it appears that PG is readily hydrated, where the most prevalent hydration interactions were found to be through both the PG hydroxyl groups but also alkyl groups typically considered hydrophobic. Hydration interactions of PG dominate the solution over PG self-self interactions and there is no evidence of more extensive association. This hydration behavior for PG in solutions suggests that the preference of PG to be hydrated rather than to be self-associated may translate into a preference for PG to bind to lipids rather than itself, providing a potential explanation for how PG is able to enhance the apparent solubility of drug molecules in vivo.

The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age.

During development, the growth of neural processes is regulated by an array of cellular and molecular mechanisms which influence growth rate, direction and branching. Recently, many members of the TNF superfamily have been shown to be key regulators of neurite growth during development. The founder member of this family, TNFα can both promote and inhibit neurite growth depending on the cellular context. Specifically, transmembrane TNFα promotes neurite growth, while soluble TNFα inhibits it. While the growth promoting effects of TNFα are restricted to a defined developmental window of early postnatal development, whether the growth inhibitory effects of soluble TNFα occur throughout development is unknown. In this study we used the extensively studied, well characterised neurons of the superior cervical ganglion to show that the growth inhibitory effects of soluble TNFα are restricted to a specific period of late embryonic and early postnatal development. Furthermore, we show that this growth inhibitory effect of soluble TNFα requires NF-κB signalling at all developmental stages at which soluble TNFα inhibits neurite growth. These findings raise the possibility that increases in the amount of soluble TNFα in vivo, for example as a result of maternal inflammation, could negatively affect neurite growth in developing neurons at specific stages of development.

Modulation of dipalmitoylphosphatidylcholine monolayers by dimethyl sulfoxide.

The action of the penetration-enhancing agent, dimethyl sulfoxide (DMSO), on phospholipid monolayers was investigated at the air-water interface using a combination of experimental techniques and molecular dynamics simulations. Brewster angle microscopy revealed that DPPC monolayers remained laterally homogeneous at subphase concentrations up to a mole fraction of 0.1 DMSO. Neutron reflectometry of the monolayers in combination with isotopic substitution enabled the determination of solvent profiles as a function of distance perpendicular to the interface for the different DMSO subphase concentrations. These experimental results were compared to those obtained from molecular dynamic (MD) simulations of the corresponding monolayer systems. There was excellent agreement found between the MD-derived reflectivity curves and the measured data for all of the H/D contrast variations investigated. The MD provide a detailed description of the distribution of water and DMSO molecules around the phosphatidylcholine headgroup, and how this distribution changes with increasing DMSO concentrations. Significantly, the measurements and simulations that are reported here support the hypothesis that DMSO acts by dehydrating the phosphatidylcholine headgroup, and as such provide the first direct evidence that it does so primarily by displacing water molecules bound to the choline group.

Enhancing equity in access to automated insulin delivery systems in an ethnically and socioeconomically diverse group of children with type 1 diabetes.

INTRODUCTION: Manufacturer-supported didactic teaching programmes offer effective automated insulin delivery (AID) systems onboarding in children and young people (CYP) with type 1 diabetes (T1D). However, this approach has limited flexibility to accommodate the needs of families requiring additional support. RESEARCH DESIGN AND METHODS: Evaluate the efficacy of an inperson manufacturer-supported didactic teaching programme (Group A), in comparison to a flexible flipped learning approach delivered virtually or inperson (Group B). Retrospective analysis of CYP with T1D using continuous glucose monitoring (CGM), who were initiated on AID systems between 2021 and 2023. Compare CGM metrics from baseline to 90 days for both groups A and B. Additionally, compare the two groups for change in CGM metrics over the 90-day period (∆), patient demographics and onboarding time. RESULTS: Group A consisted of 74 CYP (53% male) with median age of 13.9 years and Group B 91 CYP (54% male) with median age of 12.7 years. From baseline to 90 days, Group A lowered mean (±SD) time above range (TAR, >10.0 mmol/L) from 47.6% (±15.0) to 33.2% (±15.0) (p<0.001), increased time in range (TIR, 3.9-10.0 mmol/L) from 50.4% (±14.0) to 64.7% (±10.2) (p<0.001). From baseline to 90 days, Group B lowered TAR from 51.3% (±15.1) to 34.5% (±11.3) (p<0.001) and increased TIR from 46.5% (±14.5) to 63.7% (±11.0) (p<0.001). There was no difference from baseline to 90 days for time below range (TBR, <3.9 mmol/L) for Group A and Group B. ∆ TAR, TIR and TBR for both groups were comparable. Group B consisted of CYP with higher socioeconomic deprivation, greater ethnic diversity and lower carer education achievement (p<0.05). The majority of Group B (n=79, 87%) chose virtual flipped learning, halving diabetes educator time and increasing onboarding cadence by fivefold. CONCLUSIONS: A flexible virtual flipped learning programme increases onboarding cadence and capacity to offer equitable AID system onboarding.

Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Steps Ahead: Optimising physical activity in adults with cystic fibrosis: A pilot randomised trial using wearable technology, goal setting and text message feedback.

BACKGROUND: Regular participation in physical activity (PA) is encouraged for people with Cystic Fibrosis (CF). This study aimed to assess the effectiveness of an intervention using wearable technology, goal setting and text message feedback on PA and health outcomes in people with CF. METHODS: This was a pilot randomised trial conducted at University Hospital Limerick. Participants were randomly assigned to the intervention (INT) or active comparator (AC). The 12-week intervention consisted of wearable technology (Fitbit Charge 2) which was remotely monitored, and participants set step count goals. Participants were sent a one-way text message once a week over 12 weeks to positively reinforce and encourage PA participation. The AC group received the wearable technology alone. Follow up was assessed at 24 weeks. Outcomes assessed were PA, aerobic capacity, lung function, sleep, quality of life and wellbeing. RESULTS: Step count increased significantly for the INT group over 12 weeks when compared to the AC group (p=0.019). The INT group had a 28% week-to-week percentage change (Weeks 1-12), while the AC group reduced by 1%, p=0.023. Within group changes demonstrated that VO2 peak (ml/kg/min) significantly increased for the INT group at 12 weeks (24.4 ±7.65 to 26.13 ±7.79, p=0.003) but not at 24 weeks (24.45 ±7.05, p=0.776). There were no significant differences observed for VO2 peak (ml/kg/min) for the AC group. There was no significant effect on lung function, sleep, well-being, or quality of life for either group. CONCLUSIONS: A personalised PA intervention using wearable technology, goal setting and text message feedback increased PA and aerobic capacity in people with CF. Integration of this intervention into usual care may encourage regular PA participation for people with CF.

A combined proteomics and bioinformatics analysis of ZNHIT1-interacting proteins reveals a significant enrichment in proteins associated with mitochondrial function.

Adenosine 5'-triphosphate (ATP) is the principal source of cellular energy, which is essential for neuronal health and maintenance. Parkinson's disease (PD) and other neurodegenerative disorders are characterised by impairments in mitochondrial function and reductions in cellular ATP levels. Thus there is a need to better understand the biology of intracellular regulators of ATP production, in order to inform the development of new neuroprotective therapies for diseases such as PD. One such regulator is Zinc finger HIT-domain containing protein 1 (ZNHIT1). ZNHIT1 is an evolutionarily-conserved component of a chromatin-remodelling complex, which has been recently shown to increase cellular ATP production in SH-SY5Y cells and to protect against impairments in mitochondrial function caused by alpha-synuclein, a protein which is integral to PD pathophysiology. This effect of ZNHIT1 on cellular ATP production is thought to be due to increased expression of genes associated with mitochondrial function, but it is also possible that ZNHIT1 regulates mitochondrial function by binding to mitochondrial proteins. To examine this question, we performed a combined proteomics and bioinformatics analysis to identify ZNHIT1-interacting proteins in SH-SY5Y cells. We report that ZNHIT1-interacting proteins are significantly enriched in multiple functional categories, including mitochondrial transport, ATP synthesis and ATP-dependent activity. Furthermore we also report that the correlation between ZNHIT1 and dopaminergic markers is reduced in the PD brain. These data suggest that the reported beneficial effects of ZNHIT1 on ATP production may be mediated, at least in part, by its direct interaction with mitochondrial proteins and suggest that potential alterations in ZNHIT1 in PD may contribute to the known impairments in ATP generation in midbrain dopaminergic neurons in PD.

Rab11-FIP3 is a cell cycle-regulated phosphoprotein.

BACKGROUND: Rab11 and its effector molecule, Rab11-FIP3 (FIP3), associate with recycling endosomes and traffic into the furrow and midbody of cells during cytokinesis. FIP3 also controls recycling endosome distribution during interphase. Here, we examine whether phosphorylation of FIP3 is involved in these activities. RESULTS: We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. Over-expression of FIP3-S102D increased the frequency of binucleate cells consistent with a role for this phospho-acceptor site in cytokinesis. Mutation of S-280, S-347 or S-450 or other previously identified phospho-acceptor sites (S-488, S-538, S-647 and S-648) was without effect on binucleate cell formation and did not modulate the distribution of FIP3 during the cell cycle. In an attempt to identify a functional role for FIP3 phosphorylation, we report that the change in FIP3 distribution from cytosolic to membrane-associated observed during progression from anaphase to telophase is accompanied by a concomitant dephosphorylation of FIP3. However, the phospho-acceptor sites identified here did not control this change in distribution. CONCLUSIONS: Our data thus identify FIP3 as a cell cycle regulated phosphoprotein and suggest dephosphorylation of FIP3 accompanies its translocation from the cytosol to membranes during telophase. S102 is dephosphorylated during telophase; mutation of S102 exerts a modest effect on cytokinesis. Finally, we show that de/phosphorylation of the phospho-acceptor sites identified here (S-102, S-280, S-347 and S-450) is not required for the spatial control of recycling endosome distribution or function.

Exposure of foetal neural progenitor cells to IL-1ß impairs their proliferation and alters their differentiation - a role for maternal inflammation?

During pregnancy, activation of the maternal immune system results in inflammation in the foetal nervous system. The causative agents are pro-inflammatory cytokines like interleukin-1ß (IL-1ß), produced by the foetus. In this study, we examine the effect of IL-1ß on the proliferation and differentiation of neural progenitor cells (NPCs) to better understand its potential effects on the developing brain. We find that the IL-1ß receptor (IL-1R1) is expressed in the ventral mesencephalon of the developing brain. Furthermore, IL-1R1 is expressed on Nestin-positive, Sox-2-positive NPCs. IL-1ß treatment reduced the numbers of proliferating NPCs, an effect prevented by the IL-1R1 receptor antagonist. LDH and MTT assays, and western blot analysis for cleaved caspase 3 and poly(ADP-ribose) polymerase, confirmed that this was not due to an increase in cell death but rather an induction of differentiation. To further study the effects of IL-1ß on cell fate determination, we differentiated NPCs in the presence and absence of IL-1ß. Il-1ß promoted gliogenesis and inhibited neurogenesis, an effect that required p38-MAPK kinase signalling. In summary, these data show that exposure of NPCs to IL-1ß affects their development. This necessitates an examination of the consequences that maternal immune system activation during pregnancy has on the cellular architecture of the developing brain.

Vesicle trafficking and membrane remodelling in cytokinesis.

All cells complete cell division by the process of cytokinesis. At the end of mitosis, eukaryotic cells accurately mark the site of division between the replicated genetic material and assemble a contractile ring comprised of myosin II, actin filaments and other proteins, which is attached to the plasma membrane. The myosin-actin interaction drives constriction of the contractile ring, forming a cleavage furrow (the so-called 'purse-string' model of cytokinesis). After furrowing is completed, the cells remain attached by a thin cytoplasmic bridge, filled with two anti-parallel arrays of microtubules with their plus-ends interdigitating in the midbody region. The cell then assembles the abscission machinery required for cleavage of the intercellular bridge, and so forms two genetically identical daughter cells. We now know much of the molecular detail of cytokinesis, including a list of potential genes/proteins involved, analysis of the function of some of these proteins, and the temporal order of their arrival at the cleavage site. Such studies reveal that membrane trafficking and/or remodelling appears to play crucial roles in both furrowing and abscission. In the present review, we assess studies of vesicular trafficking during cytokinesis, discuss the role of the lipid components of the plasma membrane and endosomes and their role in cytokinesis, and describe some novel molecules implicated in cytokinesis. The present review covers experiments performed mainly on tissue culture cells. We will end by considering how this mechanistic insight may be related to cytokinesis in other systems, and how other forms of cytokinesis may utilize similar aspects of the same machinery.

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson's disease.

Parkinson's disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson's disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson's disease. We discuss new work on growth/differentiation factor 5's mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson's disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson's disease.

Gene Co-expression Analysis of the Human Substantia Nigra Identifies ZNHIT1 as an SNCA Co-expressed Gene that Protects Against α-Synuclein-Induced Impairments in Neurite Growth and Mitochondrial Dysfunction in SH-SY5Y Cells.

Parkinson's disease (PD) is neurodegenerative disorder with the pathological hallmarks of progressive degeneration of midbrain dopaminergic neurons from the substantia nigra (SN), and accumulation and spread of inclusions of aggregated α-synuclein (α-Syn). Since current PD therapies do not prevent neurodegeneration, there is a need to identify therapeutic targets that can prevent α-Syn-induced reductions in neuronal survival and neurite growth. We hypothesised that genes that are normally co-expressed with the α-Syn gene (SNCA), and whose co-expression pattern is lost in PD, may be important for protecting against α-Syn-induced dopaminergic degeneration, since broken correlations can be used as an index of functional misregulation. Gene co-expression analysis of the human SN showed that nuclear zinc finger HIT-type containing 1 (ZNHIT1) is co-expressed with SNCA and that this co-expression pattern is lost in PD. Overexpression of ZNHIT1 was found to increase deposition of the H2A.Z histone variant in SH-SY5Y cells, to promote neurite growth and to prevent α-Syn-induced reductions in neurite growth and cell viability. Analysis of ZNHIT1 co-expressed genes showed significant enrichment in genes associated with mitochondrial function. In agreement, bioenergetic state analysis of mitochondrial function revealed that ZNHIT1 increased cellular ATP synthesis. Furthermore, α-Syn-induced impairments in basal respiration, maximal respiration and spare respiratory capacity were not seen in ZNHIT1-overexpressing cells. These data show that ZNHIT1 can protect against α-Syn-induced degeneration and mitochondrial dysfunction, which rationalises further investigation of ZNHIT1 as a therapeutic target for PD.

Accuracy of the ActivPAL and Fitbit Charge 2 in measuring step count in Cystic Fibrosis.

BACKGROUND: Physical activity (PA) is important in Cystic Fibrosis (CF) management. Fitness wearables are becoming increasingly popular as measurement tools of PA; however, the accuracy of these devices should first be evaluated. OBJECTIVE: The purpose of this study was to assess the accuracy of the ActivPAL and Fitbit Charge 2 as a measure of step count in Cystic Fibrosis. METHODS: Twenty-one participants were recruited from an adult CF Center in Ireland for a single session of testing. Participants walked for 5 min at five pre-determined speeds in a controlled testing environment (2, 2.5, 3, 3.5 and 4 miles per hour on a treadmill) and at three self-selected speeds in a corridor (slow, medium, and fast). They concurrently wore an accelerometer (ActivPAL) and fitness wearable (Fitbit Charge 2), and both were compared to visual observations. Step count is the outcome being assessed. RESULTS: The ActivPAL under-estimated step count by 0.63% across treadmill speeds and 1.1% across self-selected walking speeds. The Fitbit Charge 2 underestimated the step count by 2.97% across treadmill speeds and by 6.3% across self-selected walking speeds. Very strong correlations were found between the ActivPAL and visual observations (r: 0.93 to 0.99), while the Fitbit Charge 2 ranged from weak to very strong correlations when compared to visual observations (r: 0.34 to 0.84). CONCLUSION: The ActivPAL and Fitbit Charge 2 demonstrated acceptable validity for step count measurement in CF. These devices can be used for tracking PA during interventions in people with CF.

Physical Activity and Sedentary Behavior in Adults With Cystic Fibrosis: Association With Aerobic Capacity, Lung Function, Sleep, Well-Being, and Quality of Life.

BACKGROUND: Physical activity (PA) and sedentary behavior (SB) have marked impact on key prognostic indicators such as aerobic capacity and lung function in people with cystic fibrosis (CF) and may have associations with sleep, well-being, and health-related quality of life (HRQOL). METHODS: This observational study assessed PA, SB, aerobic capacity, spirometry, sleep, well-being, and HRQOL in adults with CF at University Hospital Limerick. PA and SB were assessed using an accelerometer that was worn for 7 days. A cardiopulmonary exercise test assessed aerobic capacity. Spirometry was performed according to American Thoracic Society guidelines. Well-being was measured by the AWESCORE, sleep quality by the Pittsburgh Sleep Quality Index (PSQI), and HRQOL using the CF Questionnaire-Revised. RESULTS: Thirty-three participants (13 males/20 females) were recruited. Mean age was 26.2 y (± 7.1 SD), with mean FEV1 72.9% of predicted (± 26.2 SD). Mean step count was 7,788 (± 3,583 SD). Over 75% of participants did not reach recommended PA targets (> 10,000 steps), with females being 25.5% less active than males. The PSQI indicated 48.5% of participants scored > 5, indicating poor sleep quality. Number of steps and SB demonstrated a moderate significant correlation with FEV1 (r = 0.45, P = .030; r = -0.37, P = .043, respectively) and sleep quality (r = -0.85, P < .001; r = 0.77, P < .001, respectively). [Formula: see text] peak expressed relative to body weight, and as a percentage of predicted, was significantly positively correlated with step count (r = 0.48, P = .007; r = 0.42, P = .02, respectively) but did not correlate with SB (P = .96). [Formula: see text] peak (L/min) strongly correlated with FEV1 (r = 0.75, P < .001). CONCLUSIONS: Most participants did not meet PA targets. PA levels correlated to aerobic capacity, FEV1, and self-reported sleep quality, and this should be considered in longitudinal studies and in PA interventions.