Biology subjects

Parr, A.

Publications and source records attributed to Parr, A..

4 recordsLinked to original sources

bioRxiv2026

CFTR function in nasal airway cells from symptomatic and asymptomatic CF heterozygotes

Structured AbstractO_ST_ABSRationaleC_ST_ABSAn estimated 25 million people worldwide have one deleterious variant in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic respiratory disease symptoms are at an increased prevalence in cystic fibrosis (CF) heterozygotes. ObjectivesDetermine the level of CFTR function in CF heterozygotes compared to individuals without CF-causing variants. Establish whether CFTR function differs between asymptomatic and symptomatic CF heterozygotes. MethodsIndividuals without respiratory symptoms or CF family history were recruited as controls. Heterozygotes were recruited from families with a CF individual harboring null alleles or c.1521_1523del (F508del) in CFTR. CFTR function was measured by short circuit current in primary human nasal epithelial cells (HNEs) from participants. Cell composition was assessed by single cell RNA sequencing. Measurements and Main ResultsCFTR function was variable in cells from control and heterozygous individuals. Mean CFTR function in asymptomatic null (8.8{+/-}0.5{micro}A/cm2 (SEM); n=30) and F508del (8.7{+/-}1.0{micro}A/cm2; n=22) heterozygotes was similar and significantly lower at 54.6% and 53.9% than controls (16.1{+/-}1.1{micro}A/cm2; n=24; p<0.0001). Mean CFTR function in symptomatic heterozygotes (8.4{+/-}1.0{micro}A/cm2; n =15) was 52.1% of controls and did not differ from asymptomatic heterozygotes (p=0.7803). Cell identities and proportions were equivalent between control and heterozygous cultures. HNEs from CF heterozygotes showed variable response to CFTR modulators. ConclusionsCFTR function in primary airway cells exhibits substantial interindividual variability and overlaps between controls and CF heterozygotes. CF heterozygotes exhibit approximately 50% of CFTR function in controls, regardless of symptom status. These findings suggest that respiratory symptoms in CF heterozygotes are influenced by factors beyond CFTR dysfunction. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSA growing body of evidence indicates that cystic fibrosis (CF) heterozygotes are at increased risk for a range of common and chronic respiratory diseases. Given that an estimated 10 million individuals in the United States are CF heterozygotes, this population may represent a substantial and underappreciated burden of CFTR-associated disease. However, CFTR function has not been well characterized in CF heterozygotes, and it remains uncertain whether observed clinical phenotypes reflect reduced CFTR activity. Resolving these issues will be essential for clarifying the pathobiology of common respiratory diseases and for evaluating the potential role of CFTR modulator therapy in symptomatic CF heterozygotes. What This Study Adds to the FieldAnalysis of 24 controls and 67 CF heterozygotes revealed substantial interindividual variability in CFTR function, as measured ex vivo in differentiated nasal airway epithelial cells. Mean CFTR function in CF heterozygotes was approximately 50% of that observed in controls. CFTR function did not differ significantly between symptomatic and asymptomatic heterozygotes. These findings suggest that reduced CFTR activity may contribute to symptom susceptibility in CF heterozygotes, but additional factors beyond CFTR dysfunction are likely required for the development of CF-like features. Ethical approval and participant consent statementAll participants provided written consent to the research study under IRB00116966 and/or IRB00235883 and consented to have their anonymized data published. All research was conducted in a fair and ethical manner.

genetics↗

bioRxiv2023

Aperiodic EEG and 7T MRSI evidence for maturation of E/I balance supporting the development of working memory through adolescence

Postmortem animal and human models suggest changes through adolescence in aspects of excitatory glutamatergic and inhibitory GABAergic function (E/I) in prefrontal cortex (PFC) suggestive of critical period plasticity at a time of significant cognitive development. Recently, using high field 7T Magnetic Resonance Spectroscopic Imaging (MRSI), we found in vivo evidence for increases in PFC glutamate/GABA balance through adolescence into adulthood. We now extend these MRSI findings by investigating, in the same 164 10- 32-year-old participants, its correspondence with EEG aperiodic activity, an independent measure of E/I balance elucidating changes in neural activity. Results showed decreases in PFC aperiodic activity from adolescence to adulthood, that were associated with MRSI measures of glutamate/GABA balance as well as mediating the association between age and EEG aperiodic activity. Further, changes in aperiodic activity predicted performance on a working memory task, indicating a role for E/I based changes in PFC signaling mechanisms in supporting maturation of cognitive control. Taken together, these results suggest that PFC is undergoing critical period plasticity through adolescence evident in both neurotransmitter and neural function that supports cognitive development.

neuroscience↗

bioRxiv2023

Multivariate and Regional Age-Related Change in Basal Ganglia Iron in Neonates

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in rsfMRI, associated with dopaminergic processing. We used data from the Developing Human Connectome Project (N=464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [Range: 24.29-42.29] but found positive associations with postnatal age [Range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA<35 weeks) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

neuroscience↗

bioRxiv2022

Changes in gamma bursts supporting working memory development through adolescence derived from EEG spectral processing

Adolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65 Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, it did not appear to change during the delay period resulting in an increasing difference between the number of events during fixation and delay period with development, suggesting that as working memory develops there is greater specificity for gamma events supporting working memory. While average power of the transient gamma events was found to mediate age-related changes in total gamma power, the number of gamma events was unrelated to total power, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.

neuroscience↗