The mouse cortical collecting duct cell line presents a tight epithelium with regulated ion and water transport. The epithelial sodium channel (ENaC) is localized in the apical membrane and ...constitutes the rate-limiting step for sodium entry, thereby enabling transepithelial transport of sodium ions. The membrane-bound serine protease
is co-expressed with the alpha subunit of ENaC. αENaC gene expression followed the
expression, and the absence of Tmprss2 resulted not only in down-regulation of αENaC gene and protein expression but also in abolished transepithelial sodium transport. In addition, RNA-sequencing analyses unveiled drastic down-regulation of the membrane-bound protease CAP3/St14, the epithelial adhesion molecule EpCAM, and the tight junction proteins claudin-7 and claudin-3 as also confirmed by immunohistochemistry. In summary, our data clearly demonstrate a dual role of Tmprss2 in maintaining not only ENaC-mediated transepithelial but also EpCAM/claudin-7-mediated paracellular barrier; the tight epithelium of the mouse renal mCCD cells becomes leaky. Our working model proposes that Tmprss2 acts via CAP3/St14 on EpCAM/claudin-7 tight junction complexes and through regulating transcription of αENaC on ENaC-mediated sodium transport.
The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies ...of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.
•BNST and CeA calcium activity increases during drinking of alcohol and other fluids.•BNST and CeA dynorphin neurons are engaged during alcohol consumption.•BNST and CeA activity is higher when taste stimuli are novel.•BNST and CeA calcium activity during drinking is reduced after chronic alcohol.•BNST-CeA coherence is increased during alcohol drinking bouts in male mice.
We examined the performance of a simple algorithm to accurately distinguish cases of diagnosed obstructive sleep apnea (OSA) and noncases using the electronic health record (EHR) across six health ...systems in the United States.
Retrospective analysis of EHR data was performed. The algorithm defined cases as individuals with ≥ 2 instances of specific International Classification of Diseases (ICD)-9 and/or ICD-10 diagnostic codes (327.20, 327.23, 327.29, 780.51, 780.53, 780.57, G4730, G4733 and G4739) related to sleep apnea on separate dates in their EHR. Noncases were defined by the absence of these codes. Using chart reviews on 120 cases and 100 noncases at each site (n = 1,320 total), positive predictive value (PPV) and negative predictive value (NPV) were calculated.
The algorithm showed excellent performance across sites, with a PPV (95% confidence interval) of 97.1 (95.6, 98.2) and NPV of 95.5 (93.5, 97.0). Similar performance was seen at each site, with all NPV and PPV estimates ≥ 90% apart from a somewhat lower PPV of 87.5 (80.2, 92.8) at one site. A modified algorithm of ≥ 3 instances improved PPV to 94.9 (88.5, 98.3) at this site, but excluded an additional 18.3% of cases. Thus, performance may be further improved by requiring additional codes, but this reduces the number of determinate cases.
A simple EHR-based case-identification algorithm for diagnosed OSA showed excellent predictive characteristics in a multisite sample from the United States. Future analyses should be performed to understand the effect of undiagnosed disease in EHR-defined noncases. This algorithm has wide-ranging applications for EHR-based OSA research.
INTRODUCTION
In September 2022, The Jackson Laboratory Center for Alzheimer's and Dementia Research (JAX CADR) hosted a workshop with leading researchers in the Alzheimer's disease and related ...dementias (ADRD) field.
METHODS
During the workshop, the participants brainstormed new directions to overcome current barriers to providing patients with effective ADRD therapeutics. The participants outlined specific areas of focus. Following the workshop, each group used standard literature search methods to provide background for each topic.
RESULTS
The team of invited experts identified four key areas that can be collectively addressed to make a significant impact in the field: (1) Prioritize the diversification of disease targets, (2) enhance factors promoting resilience, (3) de‐risk clinical pipeline, and (4) centralize data management.
DISCUSSION
In this report, we review these four objectives and propose innovations to expedite ADRD therapeutic pipelines.
Reduced positive future thinking has been associated with suicidal ideation and behavior in adults, and appears to be exacerbated by negative affect. Yet, this has received little attention in youth. ...Prior research has also focused on longer-term future thinking, e.g., months and years, and relied on lab-based assessments. Using the experience sampling method (ESM), we investigated whether short-term future thinking in daily life was associated with suicidal ideation in youth and explored the role of affect in the future thinking–suicidal ideation relationship. A community sample of
N
= 722 adolescent twins and their non-twin siblings completed ESM as part of the TwinssCan study (
n
= 55 with, and
n
= 667 without, past-week suicidal ideation). Participants completed self-report questionnaires, including on past-week suicidal ideation as part of the SCL-90. Subsequently, daily future thinking was assessed each morning for six days with ESM. To investigate the relationship between daily positive future thinking and past-week suicidal ideation, we estimated a mixed-effects linear regression model with a random intercept for participant, including age and sex as covariates. The relationship between daily positive future thinking, past-week suicidal ideation, and average positive and negative affect from the previous day was investigated by estimating two separate mixed-effects linear regression models (one for negative affect, one for positive affect), with a random intercept for participant, and random slopes for average positive and negative affect. Our results showed that participants reporting higher past-week suicidal ideation also reported significantly less daily positive future thinking during the ESM period, and this association remained significant when controlling for previous-day average positive and negative affect. Higher average positive affect from the previous day was significantly associated with higher positive future thinking. Although average negative affect from the previous day was associated with lower positive future thinking, this association was not statistically significant. Our findings indicate that short-term future thinking relates to suicidal ideation among a non-clinical sample of adolescents. Future research should investigate the directionality of the future thinking–suicidal ideation relationship, in order to investigate whether impaired future thinking may be an early warning signal for escalating suicidal ideation in youth.
Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here, we show that kappa opioid receptor signaling in the bed ...nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.
Numerous genes are implicated in autism spectrum disorder (ASD). ASD encompasses a wide-range and severity of symptoms and co-occurring conditions; however, the details of how genetic variation ...contributes to phenotypic differences are unclear. This creates a challenge for translating genetic evidence into clinically useful knowledge. Sleep disturbances are particularly prevalent co-occurring conditions in ASD, and genetics may inform treatment. Identifying convergent mechanisms with evidence for dysfunction that connect ASD and sleep biology could help identify better treatments for sleep disturbances in these individuals.
To identify mechanisms that influence risk for ASD and co-occurring sleep disturbances, we analyzed whole exome sequence data from individuals in the Simons Simplex Collection (n = 2380). We predicted protein damaging variants (PDVs) in genes currently implicated in either ASD or sleep duration in typically developing children. We predicted a network of ASD-related proteins with direct evidence for interaction with sleep duration-related proteins encoded by genes with PDVs. Overrepresentation analyses of Gene Ontology-defined biological processes were conducted on the resulting gene set. We calculated the likelihood of dysfunction in the top overrepresented biological process. We then tested if scores reflecting genetic dysfunction in the process were associated with parent-reported sleep duration.
There were 29 genes with PDVs in the ASD dataset where variation was reported in the literature to be associated with both ASD and sleep duration. A network of 108 proteins encoded by ASD and sleep duration candidate genes with PDVs was identified. The mechanism overrepresented in PDV-containing genes that encode proteins in the interaction network with the most evidence for dysfunction was cerebral cortex development (GO:0,021,987). Scores reflecting dysfunction in this process were associated with sleep durations; the largest effects were observed in adolescents (p = 4.65 × 10
).
Our bioinformatic-driven approach detected a biological process enriched for genes encoding a protein-protein interaction network linking ASD gene products with sleep duration gene products where accumulation of potentially damaging variants in individuals with ASD was associated with sleep duration as reported by the parents. Specifically, genetic dysfunction impacting development of the cerebral cortex may affect sleep by disrupting sleep homeostasis which is evidenced to be regulated by this brain region. Future functional assessments and objective measurements of sleep in adolescents with ASD could provide the basis for more informed treatment of sleep problems in these individuals.
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