Determination of pharmacological inhibition of ALDH2 by ethanol clearance in mice.

OBJECTIVES: Retinoic acid plays diverse physiological and pathophysiological roles in reproduction, immune function, energy metabolism and carcinogenesis. Because of the potential benefits of inhibiting retinoic acid biosynthesis in certain disease states, efforts are underway to develop inhibitors of retinoic acid biosynthesis via inhibition of the aldehyde dehydrogenase-1 A (ALDH1A) family of enzymes. However, many potential ALDH1A inhibitors also inhibit the related ALDH2 enzyme that plays a role in the metabolism of ethanol. Accurate in vitro assessment of ALDH2 inhibition is problematic, and to date, there are no published in vivo assays to determine inhibition of ALDH2 by candidate ALDH1A inhibitors. STUDY DESIGN: To address this, we developed a novel gas-chromatography-mass-spectrometry ethanol clearance assay in mice using orally administered ethanol and serial measurement of ethanol over time. We then used this assay to determine pharmacological inhibition of ALDH2 by candidate ALDH1A inhibitors. RESULTS: Ethanol clearance in untreated male mice occurs within sixty minutes. Male mice treated with WIN 18,446, a known ALDH1A inhibitor that also inhibits ALDH2, demonstrated significant inhibition of ethanol clearance compared to untreated controls. Novel pyrazole and piperazine ALDH1A inhibitors were then tested with the piperazine inhibitor demonstrating ALDH2 inhibition via impaired ethanol clearance while the pyrazole inhibitor did not interfere with ethanol metabolism, suggesting a lack of ALDH2 inhibition. CONCLUSIONS: Inhibition of ethanol clearance is a useful in vivo method of inferring pharmacologic inhibition of hepatic ALDH2. This assay may be useful in the development of novel ALDH1A specific inhibitors for a variety of therapeutic indications.

Reliably Measuring Learning-Dependent Distractor Suppression with Eye Tracking.

In the field of psychological science, behavioral performance in computer-based cognitive tasks often exhibits poor reliability. The absence of reliable measures of cognitive processes contributes to non-reproducibility in the field and impedes investigation of individual differences. Specifically in visual search paradigms, response time-based measures have shown poor test-retest reliability and internal consistency across attention capture and distractor suppression, but one study has demonstrated the potential for oculomotor measures to exhibit superior reliability. Therefore, in this study, we investigated three datasets to compare the reliability of learning-dependent distractor suppression measured via distractor fixations (oculomotor capture) and latency to fixate the target (fixation times). Our findings reveal superior split-half reliability of oculomotor capture compared to that of fixation times regardless of the critical distractor comparison, with the reliability of oculomotor capture in most cases falling within the range that is acceptable for the investigation of individual differences. We additionally find that older adults have superior oculomotor reliability compared with young adults, potentially addressing a significant limitation in the aging literature of high variability in response time measures due to slower responses. Our findings highlight the utility of measuring eye movements in the pursuit of reliable indicators of distractor processing and the need to further test and develop additional measures in other sensory domains to maximize statistical power, reliability, and reproducibility.

Eye movements reveal age differences in how arousal modulates saliency priority but not attention processing speed.

The arousal-biased competition theory posits that inducing arousal increases attentional priority of salient stimuli while reducing priority of non-pertinent stimuli. However, unlike in young adults, older adults rarely exhibit shifts in priority under increased arousal, and prior studies have proposed different neural mechanisms to explain how arousal differentially modulates selective attention in older adults. Therefore, we investigated how the threat of unpredictable shock differentially modulates attentional control mechanisms in young and older adults by observing eye movements. Participants completed two oculomotor search tasks in which the salient distractor was typically captured by attention (singleton search) or proactively suppressed (feature search). We found that arousal did not modulate attentional priority for any stimulus among older adults nor affect the speed of attention processing in either age group. Furthermore, we observed that arousal modulated pupil sizes and found a correlation between evoked pupil responses and oculomotor function. Our findings suggest age differences in how the locus coeruleus-noradrenaline system interacts with neural networks of attention and oculomotor function.

Aging impairs reactive attentional control but not proactive distractor inhibition.

Older adults tend to be more prone to distraction compared with young adults, and this age-related deficit has been attributed to a deficiency in inhibitory processing. However, recent findings challenge the notion that aging leads to global impairments in inhibition. To reconcile these mixed findings, we investigated how aging modulates multiple mechanisms of attentional control by tracking the timing and direction of eye movements. When engaged in feature-search mode and proactive distractor suppression, older adults made fewer first fixations to the target but inhibited the task-irrelevant salient distractor as effectively as did young adults. However, when engaged in singleton-search mode and required to reactively disengage from the distractor, older adults made significantly more first saccades toward the task-irrelevant salient distractor and showed increased fixation times in orienting to the target, longer dwell times on incorrect saccades, and increased saccadic reaction times compared with young adults. Our findings reveal that aging differently impairs attentional control depending on whether visual search requires proactive distractor suppression or reactive distractor disengagement. Furthermore, our oculomotor measures reveal both age-related deficits and age equivalence in various mechanisms of attention, including goal-directed orienting, selection history, disengagement, and distractor inhibition. These findings help explain why conclusions of age-related declines or age equivalence in mechanisms of attentional control are task specific and reveal that older adults do not exhibit global impairments in mechanisms of inhibition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Return to fertility, toxicology, and transgenerational impact of treatment with WIN 18,446, a potential male contraceptive, in mice.

OBJECTIVES: We examined the return to fertility and transgenerational impact of treatment with WIN 18,446, an experimental male contraceptive, in mice. STUDY DESIGN: We paired male mice treated with WIN 18,446 for 4 weeks to suppress spermatogenesis, followed by a 9-week recovery, and mated them with normal females to assess fertility. F1 generation mice were subsequently mated to ascertain any transgenerational impact of treatment on fertility. Testes were examined histologically. RESULTS: WIN 18,446-treated mice and their progeny produced normally sized litters (6.5 pups per litter after treatment and 7.3 pups per litter from the progeny). However, testes histology revealed rare residual intratesticular foci of mineralization after treatment. CONCLUSIONS: Fertility normalizes after WIN 18,446 treatment, and progeny also have normal fertility.

Comparative Analysis of the Clinical Presentation of Individuals Who Test Positive or Negative for SARS-CoV-2: Results from a Test Street Study.

The common cold, the flu, and the 2019 coronavirus disease (COVID-19) have many symptoms in common. As such, without testing for severe-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV-2), it is difficult to conclude whether or not one is infected with SARS-CoV-2. The aim of the current study was to compare the presence and severity of COVID-19-related symptoms among those who tested positive or negative for the beta variant of SARS-CoV-2 (B.1.351) and identify the clinical presentation with the greatest likelihood of testing positive for SARS-CoV-2. n = 925 individuals that were tested for SARS-CoV-2 at Dutch mass testing sites (i.e., test streets) were invited to complete a short online survey. The presence and severity of 17 COVID-19-related symptoms were assessed. In addition, mood, health correlates, and quality of life were assessed for the week before the test. Of the sample, n = 88 tested positive and n = 837 tested negative for SARS-CoV-2. Individuals who tested positive for SARS-CoV-2 reported experiencing a significantly greater number, as well as greater overall symptom severity, compared to individuals who tested negative for SARS-CoV-2. A binary logistic regression analysis revealed that increased severity levels of congestion, coughing, shivering, or loss of smell were associated with an increase in the odds of testing positive for SARS-CoV-2, whereas an increase in the severity levels of runny nose, sore throat, or fatigue were associated with an increase in the odds of testing negative for SARS-CoV-2. No significant differences in mood or health correlates were found between those who tested positive or negative for SARS-CoV-2, except for a significantly higher stress score among those who tested negative for SARS-CoV-2. In conclusion, individuals that tested positive for SARS-CoV-2 experienced a significantly greater number and more severe COVID-19-related symptoms compared to those who tested negative for SARS-CoV-2. Experiencing shivering and loss of smell may be the best indicators for increased likelihood of testing positive for SARS-CoV-2.

Clarifying the pathway from anxiety sensitivity to binge eating: The mediating role of depressive symptoms in a 3-week, 3-wave longitudinal study of undergraduates.

Anxiety sensitivity (AS) - characterized by a persistent fear that arousal-related bodily sensations will lead to serious cognitive, physical, and/or social consequences - is associated with various psychopathologies, including depressive symptoms and binge eating. This 3-week, 3-wave longitudinal study examined the relation between AS (including its global AS factor and lower-order AS cognitive, physical, and social concern dimensions), depressive symptoms, and binge eating among 410 undergraduates from two universities. Using generalized estimating equation models, we found that global AS, AS social concerns, and depressive symptoms predicted binge eating during any given week. Mediation analyses showed that global AS (as a latent variable with its lower-order AS dimensions as indicators), AS cognitive concerns, and AS physical concerns at Wave 1 predicted subsequent increases in depressive symptoms at Wave 2, which, in turn, led to increases in binge eating at Wave 3. Findings contribute to a better understanding of the interplay between AS, depressive symptoms, and binge eating, highlighting the role of binge eating as a potential coping mechanism for individuals with high AS, particularly in managing depressive symptoms. This study underscores the importance of AS-targeted intervention and prevention efforts in addressing depressive symptoms and binge eating.

Eighteen-Month Outcomes Among Pregnant and Nonpregnant Reproductive-Aged People Hospitalized for Coronavirus Disease 2019.

Background: Physiologic and immunologic adaptations in pregnancy may increase the risk of adverse outcomes from respiratory viral infections. However, data are limited on longer-term outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy prior to widespread vaccine availability. Methods: Using electronic health record data, we retrospectively compared 6-, 12-, and 18-month outcomes including death and rehospitalization between pregnant and nonpregnant reproductive-aged individuals hospitalized for SARS-CoV-2 infection between 2020 and 2021 at 2 academic referral hospitals. Results: There were 190 nonpregnant and 70 pregnant participants. Mean age was 31 years for pregnant and 34 years for nonpregnant participants. For pregnant patients, mean gestational age at coronavirus disease 2019 (COVID-19) diagnosis was 36 weeks, 54% delivered by cesarean, and 97% delivered a live birth. Compared to pregnant participants, nonpregnant participants had a higher prevalence of baseline comorbidities and a higher proportion received mechanical ventilation (84% vs 55%). Index hospitalization complications (31% vs 17%) and mortality (3% vs 0%) were more common in nonpregnant participants. Over 18 months following index hospitalization, 39 (21%) nonpregnant and 5 (7%) pregnant participants were readmitted, most for infection (28/44 [64%]). Most readmissions occurred within 6 months. There were no posthospitalization deaths in the pregnant group. Conclusions: Pregnant people with severe COVID-19 disease had a low rate of severe adverse outcomes after index hospitalization. The low readmission rate is reassuring that pregnant individuals may not be at higher risk for long-term severe adverse health outcomes after COVID-19 compared to the nonpregnant reproductive-aged population, possibly because any increased risk conferred by pregnancy resolves soon after delivery.

Heart rate and breathing effects on attention and memory (HeartBEAM): study protocol for a randomized controlled trial in older adults.

BACKGROUND: In healthy people, the "fight-or-flight" sympathetic system is counterbalanced by the "rest-and-digest" parasympathetic system. As we grow older, the parasympathetic system declines as the sympathetic system becomes hyperactive. In our prior heart rate variability biofeedback and emotion regulation (HRV-ER) clinical trial, we found that increasing parasympathetic activity through daily practice of slow-paced breathing significantly decreased plasma amyloid-ß (Aß) in healthy younger and older adults. In healthy adults, higher plasma Aß is associated with greater risk of Alzheimer's disease (AD). Our primary goal of this trial is to reproduce and extend our initial findings regarding effects of slow-paced breathing on Aß. Our secondary objectives are to examine the effects of daily slow-paced breathing on brain structure and the rate of learning. METHODS: Adults aged 50-70 have been randomized to practice one of two breathing protocols twice daily for 9 weeks: (1) "slow-paced breathing condition" involving daily cognitive training followed by slow-paced breathing designed to maximize heart rate oscillations or (2) "random-paced breathing condition" involving daily cognitive training followed by random-paced breathing to avoid increasing heart rate oscillations. The primary outcomes are plasma Aß40 and Aß42 levels and plasma Aß42/40 ratio. The secondary outcomes are brain perivascular space volume, hippocampal volume, and learning rates measured by cognitive training performance. Other pre-registered outcomes include plasma pTau-181/tTau ratio and urine Aß42. Recruitment began in January 2023. Interventions are ongoing and will be completed by the end of 2023. DISCUSSION: Our HRV-ER trial was groundbreaking in demonstrating that a behavioral intervention can reduce plasma Aß levels relative to a randomized control group. We aim to reproduce these findings while testing effects on brain clearance pathways and cognition. TRIAL REGISTRATION: ClinicalTrials.gov NCT05602220. Registered on January 12, 2023.

Noradrenaline: Can we now directly measure in humans?

Measuring noradrenergic activity in the human brain has been limited to indirect assessments through pupillometry and scalp-recorded event-related potentials. A novel study has demonstrated the capability to directly measure sub-second noradrenaline dynamics using surgically implanted electrodes.