Scholarly Works, Fralin Biomedical Research Institute at VTC

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Research articles, presentations, and other scholarship


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  • Temporal dynamics of the multi-omic response to endurance exercise training
    MoTrPAC Study Group; Yan, Zhen (Nature Research, 2024-05-01)
    Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository (
  • Editorial: Effects of performing arts training on the brain, (socio)cognitive and motor functions across the lifespan
    Kausel, Leonie; Basso, Julia C.; Grinspun, Noemí; Alain, Claude (Frontiers Media, 2023-12-06)
    Performing arts are a cultural expression that is ubiquitous around the world and consists of arts that are performed for an audience, such as music, dance, and drama. In recent years, there has been a growing interest in understanding how this expressive, and in essence social activity, impacts brain development and plasticity. This topic aimed to collect evidence on how the brain and (socio)cognitive and motor functions are influenced by performing arts training along the lifespan, deepening the current knowledge on this subject and helping to unravel the neurobiological mechanisms that underlie these changes. The five articles presented in this Research Topic explore research on an acting intervention, cover matters related to dance training, identify variables related to music sophistication, and focus on performing arts and musical training.
  • Granular retrosplenial cortex layer 2/3 generates high-frequency oscillations dynamically coupled with hippocampal rhythms across brain states
    Arndt, Kaiser C.; Gilbert, Earl T.; Klaver, Lianne M.F.; Kim, Jongwoon; Buhler, Chelsea M.; Basso, Julia C.; McKenzie, Sam; English, Daniel Fine (CellPress, 2024-03-26)
    The granular retrosplenial cortex (gRSC) exhibits high-frequency oscillations (HFOs; ~150 Hz), which can be driven by a hippocampus-subiculum pathway. How the cellular-synaptic and laminar organization of gRSC facilitates HFOs is unknown. Here, we probe gRSC HFO generation and coupling with hippocampal rhythms using focal optogenetics and silicon-probe recordings in behaving mice. ChR2-mediated excitation of CaMKII-expressing cells in L2/3 or L5 induces HFOs, but spontaneous HFOs are found only in L2/3, where HFO power is highest. HFOs couple to CA1 sharp wave-ripples (SPW-Rs) during rest and the descending phase of theta. gRSC HFO current sources and sinks are the same for events during both SPW-Rs and theta oscillations. Independent component analysis shows that high gamma (50–100 Hz) in CA1 stratum lacunosum moleculare is comodulated with HFO power. HFOs may thus facilitate interregional communication of a multisynaptic loop between the gRSC, hippocampus, and medial entorhinal cortex during distinct brain and behavioral states.
  • Examining the Effect of Increased Aerobic Exercise in Moderately Fit Adults on Psychological State and Cognitive Function
    Basso, Julia C.; Oberlin, Douglas J.; Satyal, Medha K.; O’Brien, Catherine E.; Crosta, Christen; Psaras, Zach; Metpally, Anvitha; Suzuki, Wendy A. (Frontiers Media, 2022-07-12)
    Regular physical exercise can decrease the risk for obesity, diabetes, and cardiovascular disease, increase life expectancy, and promote psychological health and neurocognitive functioning. Cross-sectional studies show that cardiorespiratory fitness level (VO₂ max) is associated with enhanced brain health, including improved mood state and heightened cognitive performance. Interventional studies are consistent with these cross-sectional studies, but most have focused on low-fit populations. Few such studies have asked if increasing levels of physical activity in moderately fit people can significantly enhance mood, motivation, and cognition. Therefore, the current study investigated the effects of increasing aerobic exercise in moderately fit individuals on psychological state and cognitive performance.We randomly assigned moderately fit healthy adults, 25–59 years of age, who were engaged in one or two aerobic exercise sessions per week to either maintain their exercise regimen (n = 41) or increase their exercise regimen (i.e., 4–7 aerobic workouts per week; n = 39) for a duration of 3 months. Both before and after the intervention, we assessed aerobic capacity using a modified cardiorespiratory fitness test, and hippocampal functioning via various neuropsychological assessments including a spatial navigation task and the Mnemonic Similarity Task as well as self-reported measures including the Positive and Negative Affect Scale, Beck Anxiety Inventory, State-Trait Anxiety Inventory, Perceived Stress Scale, Rumination Scale, Eating Disorders Examination, Eating Attitudes Test, Body Attitudes Test, and Behavioral Regulation of Exercise Questionnaire. Consistent with our initial working hypotheses, we found that increasing exercise significantly decreased measures of negative affect, including fear, sadness, guilt, and hostility, as well as improved body image. Further, we found that the total number of workouts was significantly associated with improved spatial navigation abilities and body image as well as reduced anxiety, general negative affect, fear, sadness, hostility, rumination, and disordered eating. In addition, increases in fitness levels were significantly associated with improved episodic memory and exercise motivation as well as decreased stress and disordered eating. Our findings are some of the first to indicate that in middle-aged moderately-fit adults, continuing to increase exercise levels in an already ongoing fitness regimen is associated with additional benefits for both psychological and cognitive health.
  • Assessing Human Spatial Navigation in a Virtual Space and its Sensitivity to Exercise
    Smith, Alana J.; Tasnim, Noor; Psaras, Zach; Gyamfi, Daphne; Makani, Krishna; Suzuki, Wendy A.; Basso, Julia C. (MyJove Corporation, 2024-01-26)
    Spatial navigation (SN) is the ability to locomote through the environment, which requires an understanding of where one is located in time and space. This capacity is known to rely on the sequential firing of place cells within the hippocampus. SN is an important behavior to investigate as this process deteriorates with age, especially in neurodegenerative disorders. However, the investigation of SN is limited by the lack of sophisticated behavioral techniques to assess this hippocampal-dependent task. Therefore, the goal of this protocol was to develop a novel, real-world approach to studying SN in humans. Specifically, an active virtual SN task was developed using a cross-platform game engine. During the encoding phase, participants navigated their way through a virtual city to locate landmarks. During the remembering phase, participants remembered where these reward locations were and delivered items to these locations. Time to find each location was captured and episodic memory was assessed by a free recall phase, including aspects of place, order, item, and association. Movement behavior (x, y, and z coordinates) was assessed through an asset available in the game engine. Importantly, results from this task demonstrate that it accurately captures both spatial learning and memory abilities as well as episodic memory. Further, findings indicate that this task is sensitive to exercise, which improves hippocampal functioning. Overall, the findings suggest a novel way to track human hippocampal functioning over the course of time, with this behavior being sensitive to physical activity training paradigms.
  • Effects of a Neuroscience-Based Mindfulness Meditation Program on Psychological Health: Pilot Randomized Controlled Trial
    Lynn, Sarah; Basso, Julia C. (JMIR Publications, 2023)
    Background: Mindfulness and meditation have a rich historical tradition, and a growing scientific base of evidence supports their use in creating positive psychological and neuroplastic changes for practitioners. Although meditation can be taught in various ways, the scientific community has yet to systematically study the impact of different types of meditation on neuropsychological outcomes, especially as it pertains to digital implementation. Therefore, it is critical that the instruction of mindfulness be evidence based because meditation is being used in both scientific and clinical settings. Objective: This study investigated the use of teacher cueing and the integration of neuroscience education into a meditation program. Compassion cueing was chosen as the element of experimental manipulation because traditional lineages of Buddhist meditation teach compassion for self and others as one of the primary outcomes of meditation. We hypothesized that participants receiving compassion cueing would have enhanced neuropsychological outcomes compared with those receiving functional cueing and that gains in neuroscience knowledge would relate to positive neuropsychological outcomes. Methods: Participants (n=89) were randomized to receive either functional cueing (control group) or compassion cueing (experimental group) and engaged with five 10-minute meditation sessions a week for 4 weeks. All intervention sessions were administered through digital presentation. All participants completed ecological momentary assessments before and after the daily intervention, as well as pre- and postintervention questionnaires. Results: Participants demonstrated significant benefits over time, including increased mindfulness and self-compassion, decreased depression, and gains in neuroscience content (all P<.001); however, no significant between-group differences were found. Daily scores from each day of the intervention showed a statistically significant shift from active toward settled. Importantly, long-term increases in mindfulness were positively correlated to changes in compassion (r=0.326; P=.009) and self-compassion (r=0.424; P<.001) and negatively correlated to changes in anxiety (r=–0.266; P=.03) and depression (r=–0.271; P=.03). Finally, the acute effects of meditation were significantly correlated to the longitudinal outcomes (with a small-to-medium effect size), especially those relevant to mindfulness. Conclusions: We developed a novel neuroscience-based education–meditation program that enhanced self-regulation as evidenced by improved mindfulness, self-compassion, and mood state. Our findings demonstrate the behavioral importance of engaging with mindfulness meditation and reinforce the idea that the benefits of meditation are independent of teacher cueing behavior. Future studies will need to investigate the brain-based changes underlying these meditation-induced outcomes.
  • Selective Reduction of Socioeconomic Disparities in the Experimental Tobacco Marketplace: Effects of Cigarette and E-cigarette Flavor Restrictions
    Freitas-Lemos, Roberta; Tegge, Allison N.; Shevorykin, Alina; Tomlinson, Devin C.; Athamneh, Liqa N.; Stein, Jeffrey S.; Sheffer, Christine E.; Shields, Peter G.; Hatsukami, Dorothy K. (Oxford University Press, 2024-06)
    Introduction: Cigarette smoking accounts for >30% of the socioeconomic gap in life expectancy. Flavored restrictions claim to promote equity; however, no previous studies have compared the effect of cigarette and e-cigarette flavor restrictions among individuals who smoke with lower and higher socioeconomic status (SES). Aims and Methods: In a between-group within-subject design, individuals with lower (n = 155) and higher (n = 125) SES completed hypothetical purchasing trials in the experimental tobacco marketplace (ETM). Conditions were presented in a 2 × 2 factorial design (cigarette flavors restricted or unrestricted and e-cigarette flavors restricted or unrestricted) with increasing cigarette prices across trials. Results: Results show (1) SES differences in cigarette, e-cigarette, and NRT purchases under unrestricted policies, with lower SES showing higher cigarette demand and lower e-cigarette and NRT substitution than higher SES, (2) cigarette restrictions decreased cigarette and increased NRT purchases among lower SES, but no significant changes among higher SES, (3) decreased SES differences in cigarette demand under cigarette restrictions, but persistence under e-cigarette restrictions or their combination, (4) persistence of SES differences in e-cigarette purchases when all restrictions were enforced, and (5) waning of SES differences in NRT purchasing under all restrictions. Conclusions: Flavor restrictions differentially affected individuals based on SES. Within-group comparisons demonstrated restrictions significantly impacted lower SES, but not higher SES. Between-group comparisons showed SES differences in cigarette purchasing decreased under cigarette restrictions, but persisted under e-cigarette-restrictions or their combination. Additionally, SES differences in NRT substitution decreased under flavor restrictions. These findings highlight the utility of the ETM to investigate SES disparities. Implications: With increasing trends of socioeconomic differences in smoking prevalence and cessation rates, smoking-related health disparities are expected to continue to widen. Restricting menthol flavor in cigarettes while enhancing the availability and affordability of NRT have the potential to alleviate SES disparities in tobacco use, therefore, positively impacting health equity. However, this effect may depend on flavor availability in other tobacco products.
  • Inheritance of repressed chromatin domains during S phase requires the histone chaperone NPM1
    Escobar, Thelma M.; Yu, Jia-Ray; Liu, Sanxiong; Lucero, Kimberly; Vasilyev, Nikita; Nudler, S. Evgeny; Reinberg, Danny (American Association for the Advancement of Science, 2022-04-27)
    The epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin, and MCM2, an integral component of the DNA replication machinery; moreover, NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in the G1-S phase of the cell cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. NPM1 chaperone activity may contribute to the integrity of this process as appropriate inheritance required the NPM1 acidic patches.
  • Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta
    Pridham, Kevin J.; Hutchings, Kasen R.; Beck, Patrick; Liu, Min; Xu, Eileen; Saechin, Erin; Bui, Vincent; Patel, Chinkal; Solis, Jamie; Huang, Leah; Tegge, Allison; Kelly, Deborah F.; Sheng, Zhi (Elsevier, 2024-06-21)
    Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3K⍺/β/𝛿/𝛾 has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma’s chemosensitivity. Here,wereport that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kβ being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase(MGMT) and expressing elevated levels of PI3Kβ, defined as MGMT-deficient/PI3Kβ-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kβ-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kβ, but not other kinases, sensitized MGMTdeficient/ PI3Kβ-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kβ-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kβ in chemoresistance, making PI3Kβ-selective blockade an effective chemosensitizer for glioblastoma.
  • Measurable Residual FLT3 Internal Tandem Duplication Before Allogeneic Transplant for Acute Myeloid Leukemia
    Dillon, Laura W.; Gui, Gege; Ravindra, Niveditha; Andrew, Georgia; Mukherjee, Devdeep; Wong, Zoë C.; Huang, Ying; Gerhold, Jason; Holman, Matt; D'Angelo, Julian; Miller, Jeffrey; Higgins, Jake; Salk, Jesse J.; Auletta, Jeffrey J.; El Chaer, Firas; Devine, Steven M.; Jimenez Jimenez, Antonio Martin; De Lima, Marcos J. G.; Litzow, Mark R.; Kebriaei, Partow; Saber, Wael; Spellman, Stephen R.; Zeger, Scott L.; Page, Kristin M.; Hourigan, Christopher S. (American Medical Association, 2024-05-02)
    Importance: Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown. Objective: To examine the association between pre–allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR. Design, Setting, and Participants: In this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023. Exposure: Centralized DNA sequencing for FLT3-ITD in pre–allogeneic HCT first CR blood using a commercially available kit. Main Outcomes and Measures: The primary outcomes were overall survival and cumulative incidence of relapse, with non–relapse-associated mortality as a competing risk post–allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points. Results: Of 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning. Conclusions and Relevance: This study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.
  • Coordination of rhythmic RNA synthesis and degradation orchestrates 24-and 12-h RNA expression patterns in mouse fibroblasts
    Unruh, Benjamin A.; Weidemann, Douglas E.; Miao, Lin; Kojima, Shihoko (National Academy of Sciences, 2024)
    Circadian RNA expression is essential to ultimately regulate a plethora of downstream rhythmic biochemical, physiological, and behavioral processes. Both transcriptional and posttranscriptional mechanisms are considered important to drive rhythmic RNA expression; however, the extent to which each regulatory process contributes to the rhythmic RNA expression remains controversial. To systematically address this, we monitored RNA dynamics using metabolic RNA labeling technology during a circadian cycle in mouse fibroblasts. We find that rhythmic RNA synthesis is the primary contributor of 24-h RNA rhythms, while rhythmic degradation is more important for 12-h RNA rhythms. These rhythms were predominantly regulated by Bmal1 and/or the core clock mechanism, and the interplay between rhythmic synthesis and degradation has a significant impact in shaping rhythmic RNA expression patterns. Interestingly, core clock RNAs are regulated by multiple rhythmic processes and have the highest amplitude of synthesis and degradation, presumably critical to sustain robust rhythmicity of cell-autonomous circadian rhythms. Our study yields invaluable insights into the temporal dynamics of both 24-and 12-h RNA rhythms in mouse fibroblasts.
  • Dopamine and serotonin in human substantia nigra track social context and value signals during economic exchange
    Batten, Seth R.; Bang, Dan; Kopell, Brian H.; Davis, Arianna N.; Heflin, Matthew; Fu, Qixiu; Perl, Ofer; Ziafa, Kimia; Hashemi, Alice; Saez, Ignacio; Barbosa, Leonardo S.; Twomey, Thomas; Lohrenz, Terry; White, Jason P.; Dayan, Peter; Charney, Alexander W.; Figee, Martijn; Mayberg, Helen S.; Kishida, Kenneth T.; Gu, Xiaosi; Montague, P. Read (Nature Research, 2024-02-26)
    Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson’s disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value—akin to reward prediction errors—whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia’s main output structures reflect distinct social context and value signals.
  • PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice
    Stevens, Shaunaci A.; Aguiar, Maria K. Gonzalez; Toro, Allyson L.; Yerlikaya, Esma I.; Sunilkumar, Siddharth; VanCleave, Ashley M.; Pfleger, Jessica; Bradley, Elisa A.; Kimball, Scot R.; Dennis, Michael D. (American Physiological Society, 2022-11-16)
    Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here, we investigated the role of the stress response protein regulated in development and DNA damage 1 (REDD1) as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 wk, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the proinflammatory cytokines IL-1β, IL-6, and TNFα. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase protein kinase RNA-like endoplasmic reticulum kinase (PERK) or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced proinflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.NEW & NOTEWORTHY Interplay between endoplasmic reticulum stress and inflammation contributes to cardiovascular disease progression. The studies here identify the stress response protein known as REDD1 as a missing molecular link that connects the development of endoplasmic reticulum stress with increased production of proinflammatory cytokines in the hearts of obese mice.
  • Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease
    Brisendine, Matthew H.; Nichenko, Anna S.; Bandara, Aloka B.; Willoughby, Orion S.; Amiri, Niloufar; Weingrad, Zach; Specht, Kalyn S.; Bond, Jacob M.; Addington, Adele; Jones III, Ronald G.; Murach, Kevin A.; Poelzing, Steven; Craige, Siobhan M.; Grange, Robert W.; Drake, Joshua C. (Oxford University Press, 2023-12-04)
    Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD.
  • Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial
    Legon, Wynn; Strohman, Andrew; In, Alexander; Payne, Brighton (Wolters Kluwer Health, Inc., 2024-02-01)
    The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat–evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.
  • Hedgehog-interacting protein acts in the habenula to regulate nicotine intake
    Caligiuri, Stephanie P. B.; Howe, William M.; Wills, Lauren; Smith, Alexander C. W.; Lei, Ye; Bali, Purva; Heyer, Mary P.; Moen, Janna K.; Ables, Jessica L.; Elayouby, Karim S.; Williams, Maya; Fillinger, Clementine; Oketokoun, Zainab; Lehmann, Vanessa E.; DiFeliceantonio, Alexandra G.; Johnson, Paul M.; Beaumont, Kristin; Sebra, Robert P.; Ibanez-Tallon, Ines; Kenny, Paul J. (National Academy of Sciences, 2022-11-08)
    Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.
  • Cardiovascular aging: from cellular and molecular changes to therapeutic interventions
    Vakka, Angeliki; Warren, Junco S.; Drosatos, Konstantinos (OAE Publishing, 2023-07-01)
    Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes.
  • PERM1 regulates energy metabolism in the heart via ERR alpha/PGC-1 alpha axis
    Oka, Shin-ichi I.; Sreedevi, Karthi; Shankar, Thirupura S.; Yedla, Shreya; Arowa, Sumaita; James, Amina; Stone, Kathryn G.; Olmos, Katia; Sabry, Amira D.; Horiuchi, Amanda; Cawley, Keiko M.; O'very, Sean A.; Tong, Mingming; Byun, Jaemin; Xu, Xiaoyong; Kashyap, Sanchita; Mourad, Youssef; Vehra, Omair; Calder, Dallen; Lunde, Ty; Liu, Tong; Li, Hong; Mashchek, J. Alan; Cox, James; Saijoh, Yukio; Drakos, Stavros G.; Warren, Junco S. (Frontiers, 2022-11-07)
    Aims: PERM1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that PERM1 is downregulated in the failing heart and that PERM1 positively regulates metabolic genes known as targets of the transcription factor ERRα and its coactivator PGC-1α in cultured cardiomyocytes. The aims of this study were to determine the effect of loss of PERM1 on cardiac function and energetics using newly generated Perm1-knockout (Perm1–/–) mice and to investigate the molecular mechanisms of its transcriptional control. Methods and results: Echocardiography showed that ejection fraction and fractional shortening were lower in Perm1–/– mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1–/– hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1–/– hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1’s binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2. Conclusion: This study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.
  • Pregnancy-induced remodeling of the murine reproductive tract: a longitudinal in vivo magnetic resonance imaging study
    Suarez, Aileen C.; Gimenez, Clara J.; Russell, Serena R.; Wang, Maosen; Munson, Jennifer M.; Myers, Kristin M.; Miller, Kristin S.; Abramowitch, Steven D.; De Vita, Rafaella (Springer, 2024-01-05)
    Mammalian pregnancy requires gradual yet extreme remodeling of the reproductive organs to support the growth of the embryos and their birth. After delivery, the reproductive organs return to their non-pregnant state. As pregnancy has traditionally been understudied, there are many unknowns pertaining to the mechanisms behind this remarkable remodeling and repair process which, when not successful, can lead to pregnancy-related complications such as maternal trauma, pre-term birth, and pelvic floor disorders. This study presents the first longitudinal imaging data that focuses on revealing anatomical alterations of the vagina, cervix, and uterine horns during pregnancy and postpartum using the mouse model. By utilizing advanced magnetic resonance imaging (MRI) technology, T1-weighted and T2-weighted images of the reproductive organs of three mice in their in vivo environment were collected at five time points: non-pregnant, mid-pregnant (gestation day: 9–10), late pregnant (gestation day: 16–17), postpartum (24–72 h after delivery) and three weeks postpartum. Measurements of the vagina, cervix, and uterine horns were taken by analyzing MRI segmentations of these organs. The cross-sectional diameter, length, and volume of the vagina increased in late pregnancy and then returned to non-pregnant values three weeks after delivery. The cross-sectional diameter of the cervix decreased at mid-pregnancy before increasing in late pregnancy. The volume of the cervix peaked at late pregnancy before shortening by 24–72 h postpartum. As expected, the uterus increased in cross-sectional diameter, length, and volume during pregnancy. The uterine horns decreased in size postpartum, ultimately returning to their average non-pregnant size three weeks postpartum. The newly developed methods for acquiring longitudinal in vivo MRI scans of the murine reproductive system can be extended to future studies that evaluate functional and morphological alterations of this system due to pathologies, interventions, and treatments.
  • Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555
    Guan, Yuntian; Zhang, Mei; Lacy, Christie; Shah, Soham; Epstein, Frederick H.; Yan, Zhen (MDPI, 2024-01-03)
    Millions of diabetic patients suffer from cardiovascular complications. One of the earliest signs of diabetic complications in the heart is diastolic dysfunction. Regular exercise is a highly effective preventive/therapeutic intervention against diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Studies have shown that the accumulation of damaged or dysfunctional mitochondria in the myocardium is at the center of this pathology. Here, we employed a mouse model of diabetes to test the hypothesis that endurance exercise training mitigates diastolic dysfunction by promoting cardiac mitophagy (the clearance of mitochondria via autophagy) via S555 phosphorylation of Ulk1. High-fat diet (HFD) feeding and streptozotocin (STZ) injection in mice led to reduced endurance capacity, impaired diastolic function, increased myocardial oxidative stress, and compromised mitochondrial structure and function, which were all ameliorated by 6 weeks of voluntary wheel running. Using CRISPR/Cas9-mediated gene editing, we generated non-phosphorylatable Ulk1 (S555A) mutant mice and showed the requirement of p-Ulk1at S555 for exercise-induced mitophagy in the myocardium. However, diabetic Ulk1 (S555A) mice retained the benefits of exercise intervention. We conclude that endurance exercise training mitigates diabetes-induced diastolic dysfunction independent of Ulk1 phosphorylation at S555.