Browsing by Author "Everett, Thomas"

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    Application of Physiological Autonomic Activity Tracking GUI and Computational Algorithms for Measuring Persistent Vagal Nerve Dysfunction After Recovery from SARS‐CoV‐2 Infection
    (Wiley, 2022) Wilson, Damen A.; Nowak, Thomas; Gupta, Anita; McKinnon, Michael; Clements, Isaac; Everett, Thomas; Powley, Terry; Ward, Matthew; Medicine, School of Medicine
    Post‐Acute Sequelae of SARS‐CoV‐2 infection (PASC) is now recognized as a constellation of symptoms such as postural hypotension, anxiety, and “brain fog” in addition to autonomic nervous system dysfunction such as tachycardia and labile hypertension. Better quantification of these conditions, specifically, autonomic nervous system dysfunction, is desired for future diagnostics, treatment modalities, and gaining a further understanding of PASC. This research has led to application of a novel autonomic activity tracking algorithm and GUI suite from previous work, see Figure 1, to study the physiological autonomic activity in six patients who had recovered from acute SARS‐CoV‐2 infection a mean of six months prior but were still experiencing symptoms. By measuring skin sympathetic nervous activity (SKNA), heart rate variability, and the cutaneous electrogastrogram (EGG), all before and after a water meal challenge, the data was fed into a custom analysis pipeline, shown in Figure 1. Each of the PASC patients were compared to a mean response of 34 healthy controls, each undergoing a 20‐minute baseline recording and another 20‐minute recording after ingestion of an 8 oz water test meal. All six patients showed significantly abnormal heart rate variability on frequency domain analysis in predominantly the low frequency (LF) and very low frequency (VLF) bands, and less so in the high frequency (HF) band, suggesting sympathetic nerve dysfunction. Three patients showed a significant decrease in SKNA while two showed a significant increase. All patients showed an abnormal cutaneous EGG. As shown in Figure 2, the temporal responses of aSKNA, VLF, LF, HF, and EGG for the PASC patients revealed that on average they were statistically different (p<0.05) from the healthy controls’ responses respectively during 98.4%, 78.4%, 86.76%, 47.9%, and 86.1% of the 40‐minute time period in testing, 20 minutes of baseline and 20 minutes after ingestion. In conclusion, we are looking at the sympathetic, parasympathetic, and enteric nervous systems synced temporally for applications with classification and further stratification of PASC based on the temporal dynamics of their autonomic nervous system mediated coordination from digestion. This shows that SARS‐CoV02 infection appears to have a significant effect on sympathetic and parasympathetic autonomic nervous system function and may be responsible for the disturbances noted in PASC. This work provides the framework and example of use for further applications in autonomic disorder physiological response exploration and furthermore can be expanded to other areas of neuromodulation.
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    An N‐terminal fusion allele to study melanin concentrating hormone receptor 1
    (Wiley, 2021-08) Jasso, Kalene R.; Kamba, Tisianna K.; Zimmerman, Arthur D.; Bansal, Ruchi; Engle, Staci E.; Everett, Thomas; Wu, Chang-Hung; Kulaga, Heather; Reed, Randal R.; Berbari, Nicolas F.; McIntyre, Jeremy C.; Biology, School of Science
    Cilia on neurons play critical roles in both the development and function of the central nervous system (CNS). While it remains challenging to elucidate the precise roles for neuronal cilia, it is clear that a subset of G-protein-coupled receptors (GPCRs) preferentially localize to the cilia membrane. Further, ciliary GPCR signaling has been implicated in regulating a variety of behaviors. Melanin concentrating hormone receptor 1 (MCHR1), is a GPCR expressed centrally in rodents known to be enriched in cilia. Here we have used MCHR1 as a model ciliary GPCR to develop a strategy to fluorescently tag receptors expressed from the endogenous locus in vivo. Using CRISPR/Cas9, we inserted the coding sequence of the fluorescent protein mCherry into the N-terminus of Mchr1. Analysis of the fusion protein (mCherryMCHR1) revealed its localization to neuronal cilia in the CNS, across multiple developmental time points and in various regions of the adult brain. Our approach simultaneously produced fortuitous in/dels altering the Mchr1 start codon resulting in a new MCHR1 knockout line. Functional studies using electrophysiology show a significant alteration of synaptic strength in MCHR1 knockout mice. A reduction in strength is also detected in mice homozygous for the mCherry insertion, suggesting that while the strategy is useful for monitoring the receptor, activity could be altered. However, both lines should aid in studies of MCHR1 function and contribute to our understanding of MCHR1 signaling in the brain. Additionally, this approach could be expanded to aid in the study of other ciliary GPCRs.
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    Small Conductance Calcium-Activated Potassium Current is Activated During Hypokalemia and Masks Short Term Cardiac Memory Induced by Ventricular Pacing.
    (AHA, 2015-10-13) Chan, Yi-Hsin; Tsai, Wei-Chung; Ko, Jum-Suk; Yin, Dechun; Chang, Po-Cheng; Rubart, Michael; Weiss, James N.; Everett, Thomas; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of Medicine
    Background: Hypokalemia increases the vulnerability to ventricular fibrillation (VF). We hypothesize that the apamin-sensitive small conductance calcium-activated potassium current (IKAS) is activated during hypokalemia and that IKAS blockade is proarrhythmic. Methods and Results: Optical mapping was performed in 23 Langendorff perfused rabbit ventricles with atrioventricular block and either right ventricular (RV) or left ventricular (LV) pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD80) by 26 ms [95% confidence interval, CI, 14–37] during normokalemia and by 54 ms [CI, 40 to 68] during hypokalemia (P=0.01) at 1000 ms pacing cycle length (PCL). In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the PCL threshold of APD alternans, the PCL for wavebreak induction and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained VF (from 3/9 hearts to 9/9 hearts, P=0.009). Short term cardiac memory was assessed by the slope of APD80 versus activation time. The slope increased from 0.01 [CI, −0.09 to 0.12] at baseline to 0.34 [CI, 0.23 to 0.44] after apamin (P<0.001) during RV pacing, and from 0.07 [CI, −0.05 to 0.20] to 0.54 [CI, 0.06 to 1.03] after apamin infusion (P=0.045) during LV pacing. Patch-clamp studies confirmed increased IKASin isolated rabbit ventricular myocytes during hypokalemia (P=0.038). Conclusions: Hypokalemia activates IKAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. IKAS blockade prominently lengthens the APD at late activation sites and facilitates VF induction.