Scholarly Works, Fralin Biomedical Research Institute at VTC

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A Roadmap to Holographic Focused Ultrasound Approaches to Generate Thermal Patterns
Cengiz, Ceren; Eger, Zekeriya Ender; Acar, Pinar; Legon, Wynn; Shahab, Shima (Wiley, 2026-04)
In therapeutic focused ultrasound (FUS), such as thermal ablation and hyperthermia, effective acousto-thermal manipulation requires precise targeting of complex geometries, sound wave propagation through irregular structures and selective focusing at specific depths. Acoustic holographic lenses (AHLs) provide a distinctive capability to shape acoustic fields into precise, complex and multifocal FUS-thermal patterns. Acknowledging the underexplored potential of AHLs in shaping ultrasound-induced heating patterns, this study introduces a roadmap for acousto-thermal modeling in the design of AHLs. Three primary modeling approaches are studied and contrasted using four distinct shape groups for the imposed target field. They include pressure-based (BSC-TR and ITER-TR), temperature-based (IHTO-TR), and machine learning (ML)-based (GaN and Feat-GAN) methods. Novel metrics including image quality, thermal efficiency, control, and computational time are introduced, providing each method’s strengths and weaknesses. The importance of evaluating target pattern complexity, thermal and pressure requirements, and computational resources is highlighted for selecting the appropriate methods. For lightly heterogeneous media and targets with lower pattern complexity, BSC-TR combined with error diffusion algorithms provides an effective solution. As pattern complexity increases, ITERTR becomes more suitable, enabling optimization through iterative forward and backward propagations controlled by different error metrics. IHTO-TR is recommended for highly heterogeneous media, particularly in applications requiring thermal control and precise heat deposition. GaN is ideal for rapid solutions that account for acousto-thermal effects, especially when model parameters and boundary conditions remain constant. In contrast, Feat-GaN is effective for moderately complex shape groups and applications where model parameters must be adjusted.
Estrogen, Epigenetics, and Cardiometabolic Health: Mechanisms and Therapeutic Strategies in Postmenopausal Women
Edwards, Ailene; Singh, Pranjal; Shah, Vyan; Chander, Vivek; Mishra, Sumita (MDPI, 2026-03-16)
The loss of estrogen following menopause is associated with a marked increase in cardiometabolic risk, accompanied by adverse changes in lipid metabolism, insulin sensitivity, vascular function, and systemic inflammatory tone. Emerging evidence suggests that estrogen signaling interacts with chromatin regulatory mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, across multiple metabolic tissues. In this review, we examine current evidence linking estrogen receptor signaling to epigenetic modulation in cardiovascular, hepatic, adipose, vascular, and immune systems. We propose that epigenetic remodeling represents a plausible and testable mechanistic framework connecting estrogen depletion to cardiometabolic disease progression, while acknowledging that much of the mechanistic evidence derives from preclinical and in vitro systems and that direct longitudinal validation in human cardiovascular tissues remains limited. We further explore how this framework may contribute to understanding the “estrogen paradox” and the heterogeneous outcomes of hormone replacement therapy (HRT), particularly within the context of the timing hypothesis. Finally, we evaluate pharmacologic and lifestyle interventions, including structured exercise, dietary modulation, and cardiometabolic therapeutics, through the lens of potential epigenetic influence. Clarifying tissue-specific and immune-integrated chromatin responses to estrogen loss will be essential for advancing precision strategies aimed at improving cardiometabolic health in postmenopausal women.
Measurable residual mutated NPM1 before allogeneic transplant for acute myeloid leukemia
Al-Ali, Rasha W.; Gui, Gege; Ravindra, Niveditha; Andrew, Georgia; Mukherjee, Devdeep; Wong, Zoe C.; Huang, Ying; Gerhold, Jason; Holman, Matt; Jacobsen, Austin; D'angelo, Julian; Miller, Jeffrey; Elias, Karina; Auletta, Jeffery J.; El Chaer, Firas; Devine, Steven M.; Jimenez, Antonio Martin Jimenez; De Lima, Marcos JG G.; Litzow, Mark R.; Kebriaei, Partow; Saber, Wael; Spellman, Stephen R.; Zeger, Scott L.; Page, Kristin M.; Radich, Jerald P.; Lindsley, R. Coleman; Dillon, Laura W.; Hourigan, Christopher S. (Springer Nature, 2026-02-01)
Comparative Efficacy RCT of 3 Intensive Infant/Toddler Therapies for Unilateral Cerebral Palsy
DeLuca, Stephanie C.; Ramey, Sharon L.; Darragh, Amy R.; Conaway, Mark; Heathcock, Jill C.; Lo, Warren; Gordon, Andrew M.; Trucks, Mary Rebekah; Wallace, Dory; Cabral, Thais Invencao (American Academy of Pediatrics, 2026-02-01)
Objectives: Unilateral cerebral palsy (UCP) can result in lifelong upper extremity (UE) neuromotor impairment. While both constraint-induced movement therapy (CIMT) and bimanual training have demonstrated efficacy for children with UCP, there was limited evidence to inform treatment decision-making in children aged between 6 and 24 months. Thus, we performed a comparative efficacy trial testing 3 high-dose therapist-delivered interventions, 2 CIMT interventions varied by constraint type to bimanual/no-constraint intervention for use in treating this age group of children with UCP. Patients and Methods: Fifty-eight infants/toddlers with UCP diagnosis, aged 6 to 24 months, were enrolled and randomized. Exclusion criteria were uncontrolled seizures, fragile health, prior CIMT/bimanual therapy, and recent botulinum toxin. Participants were randomly assigned (1:1:1) to 1 of 3 treatments all delivered 3 hours/d and 5 days/wk for 4 weeks: CIMT/full-time cast, CIMT/part-time splint, or bimanual/no constraint. Anonymized assessments at baseline, end of treatment (EoT), and 6 months posttreatment included the Mini–Assisting Hand Assessment (AHA) for bimanual abilities and the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Fine-Motor (FM) subscale on each UE for FM abilities. Results: Fifty-three infant/toddlers completed treatment and EoT assessment (mean age, 17.2 months), and 41 completed 6-month assessment. All groups had gains from intervention: Mini-AHA scores (P < .003) and Bayley-III FM/paretic side (P < .002). Bayley-III FM/nonparetic side also improved across groups (P < .001). The CIMT/full-time cast showed larger gains on Bayley-III FM/nonparetic side when compared with bimanual/no constraint (difference, 5.9; 95% CI, 1.2-10.5; P = .015). Conclusion: The trial confirms comparable benefits from therapist-delivered CIMT and bimanual/no-constraint interventions for infants/toddlers with UCP aged between 6 and 24 months.
Perceived reward certainty in the assessment of delay discounting
Downey, Haylee; Alvarez, Alicia; Ji, Wenyan; Lozano, Alicia; Hanlon, Alexandra L.; Stein, Jeffrey S. (Wiley, 2025-09-09)
Reward delays are often associated with reduced probability of reward, although standard assessments of delay discounting do not specify degree of reward certainty. Thus, the extent to which estimates of delay discounting are influenced by uncontrolled variance in perceived reward certainty remains unclear. Here we examine 370 participants who were randomly assigned to complete a delay discounting task when reward certainty was either unspecified (n=184) or specified as 100% (n = 186) in the task trials and task instructions. We examined potential group differences in (a) perceived reward certainty across a range of delays, (b) delay discounting, and (c) associations between perceived reward certainty and delay discounting. Delay significantly reduced perceived reward certainty in both groups, although delay did not significantly interact with group to affect perceived certainty. Despite higher perceived reward certainty in the specified group, no significant group difference in delay discounting was observed. Higher perceived reward certainty was associated with lower delay discounting in both groups. However, we found no evidence that specifying reward certainty influences estimates of delay discounting. Future research should examine whether perceived reward certainty moderates associations between delay discounting and health behavior and whether perceived reward certainty is impacted by interventions that change delay discounting.
Sample pooling approaches simulated under resource scarcity, lapses in testing capacity, and rapid processing demands for surveillance testing: a data-driven performance comparison
Burgess, Catharine; Curran, Alan; Ceci, Alessandro; Finkielstein, Carla V.; Lahmers, Kevin K. (2026-01-30)
Background: Sample pooling is a critical strategy to meet increased testing demand and conserve resources in surveillance testing. Much of its effectiveness depends on how well optimized the pool size is to the prevalence of infection in the sampled population, which can be difficult to anticipate in many circumstances. Multiple methods exist to better optimize pooling, with unique trade-offs. Methods: Pooling optimization methods were simulated to examine trade-offs between surveillance priorities and operational characteristics using SARS-CoV-2 surveillance data and workflows generated by the Virginia Tech Molecular Diagnostics Laboratory under varying capacity conditions. All in-house validation procedures were designed and established exclusively under CLIA to ensure full control of the analytical framework and to accurately reflect true capacity constraints. We used binary surveillance data to run Monte Carlo simulations (MCS) comparing conservative and large fixed pools, historical prevalence optimization (HPO), prevalence estimation testing (PET), truly optimized pooling, and individual testing. Median test counts from the MCS fed a discrete-event simulation (DES) that assessed processing time at different lab capacities under surveillance and outbreak conditions. We then used the combined performance results to build a classification tree to guide method selection under different testing priorities and constraints. Results: MCS results indicated that small pools (4 samples), HPO, and PET resulted in test counts that were not statistically different from truly optimized pooling (p > 0.05). The DES showed that pooling methods generally performed comparably to individual testing in processing time at low laboratory capacity, but individual testing became faster as capacity increased. Across capacity conditions, individual testing processed fewer than 500 daily samples more quickly, yet it demanded more hands-on time than pooling. Large-scale surveillance favored pooled methods, which were quicker under most conditions, while outbreak scenarios often favored individual testing when capacity wasn’t highly limited. Machine learning analysis highlighted surveillance priorities and sample intake as key determinants in selecting the best pooling optimization method for the given circumstance. Conclusion: This study demonstrates the importance of maintaining multiple pooling optimization approaches and adapting strategies to match evolving demands and potential constraints in surveillance testing.
Impact of obesity on the perinatal vaginal environment and bacterial microbiome: effects on birth outcomes
Ingram, Kelly; Eko, Embelle Ngalame; Nunziato, Jaclyn; Ahrens, Monica; Howell, Brittany (Microbiology Society, 2024-08)
Introduction. Lactobacillus species predominate the human vagina and are associated with positive vaginal health, including an acidic pH (<4.5). The prevalence of vaginal Lactobacilli increases with increased oestrogen due to increased glycogen production within the vagina. Lactobacilli produce lactic acid, thereby lowering vaginal pH, preventing growth of other bacteria, and lowering microbial diversity. Lower placental oestrogen levels in obese pregnant women could dampen the mechanism to initiate this process, which may be associated with vaginal dysbiosis and unfavourable pregnancy outcomes. Hypothesis. We hypothesize that oestrogen and glycogen levels will be lower, vaginal pH will be higher, and vaginal microbiome diversity will be greater during pregnancy in obese and overweight women compared to healthy weight women. Aim. Pregnancy complications (e.g. preterm birth) are more common in overweight and obese women. If vaginal dysbiosis plays a role, and quantifiable predictors of this increased risk can be determined, these measures could be used to prospectively identify women at risk for pregnancy complications early in pregnancy. Methodology. Vaginal samples were collected at 10–14, 18–24, 26–30, and 34–37 weeks gestation and at delivery from 67 pregnant participants (23 healthy weight, 22 overweight, 22 obese). A blood sample to quantify serum oestrogen was collected at 10–14 weeks. Vaginal samples were collected to test vaginal pH using pH paper, glycogen abundance using fluorometry, and the vaginal microbiome using 16S rRNA amplicon sequencing. Results. Vaginal pH was higher in obese participants compared to healthy weight participants (P=<0.001). Vaginal glycogen levels increased over time in obese participants (P=0.033). The vaginal bacterial alpha diversity was higher in obese participants compared to healthy weight participants (P=0.033). The relative abundances of Peptoniphilus and Anaerococcus were increased in overweight and obese participants, as well as in complicated pregnancies, at 10–14 weeks gestation. Conclusion. The relative abundance of specific vaginal bacteria, like Peptoniphilus and Anaerococcus, in early pregnancy could predict pregnancy outcomes. Our goal is to use the information gathered in this pilot study to further determine the feasibility of assessing the vaginal environment during pregnancy to identify women at risk for negative pregnancy and birth outcomes in the context of a larger study.
A Feasibility Study of Real-Time FMRI with Neurofeedback of Motor Performance in Cerebellar Ataxia
Berenbaum, Joshua G.; Marvel, Cherie L.; Lisinski, Jonathan M.; Soldate, Jeffrey S.; Morgan, Owen P.; Kucharski, Ashley N.; Lutzel, Luca P.; Ecker, Jonathan A.; Rice, Laura C.; Mistri, Amy; Nadkarni, Prianca A.; Rosenthal, Liana S.; LaConte, Stephen M. (MDPI, 2026-01-23)
Background/Objectives: Neurodegenerative cerebellar ataxia (CA) is a movement disorder caused by progressive cell death in the cerebellum. Motor imagery represents a potential therapeutic tool to improve motor function by “exercising” brain regions associated with movement, without the need for overt activity. This study assessed the feasibility of combining motor imagery with real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) to improve motor function in CA. Methods: During finger tapping conditions, 16 participants with CA pushed a button at the same frequency in time with cross flashing at 1 Hz or 4 Hz, and this information was used to train the model. During motor imagery, participants imagined finger tapping while undergoing rt-fMRI-NF with visual feedback, steering them toward activating their motor circuit. Afterwards, they completed finger tapping again. FMRI analysis compared successful motor imagery trials versus all other imagery events. Brain activity on successful trials was covaried with pre–post rt-fMRI-NF tapping improvement scores. Results: Tapping was more accurate at 1 Hz than 4 Hz, and larger tapping error rates correlated with greater movement impairments. While not significant at the group level, 9 of the 16 participants improved tapping accuracy following rt-fMRI-NF. The size of motor improvements correlated with successful motor imagery activity at 1 Hz in the frontal lobe, insula, parietal lobe, basal ganglia, and cerebellum. Motor improvements were not associated with neurological impairment severity, mood, cognition, or imagery vividness. Conclusions: Feasibility was demonstrated for motor imagery therapy with neurofeedback to potentially improve fine motor precision in people with CA. Brain regions relevant to this process may be considered for targets of non-invasive therapeutic interventions.
Ampk alpha2 T172 activation dictates exercise performance and energy transduction in skeletal muscle
Montalvo, Ryan N.; Li, Xiaolu; Many, Gina M.; Sagendorf, Tyler J.; Yu, Qing; Shen, Wenqing; Wase, Nishikant; Burgardt, A. Robert; Zhang, Tong; Gritsenko, Marina A.; Gaffrey, Matthew J.; Bhonsle, Hemangi; Guan, Yuntian; Mao, Xuansong; Zhang, Mei; Qian, Wei-Jun; Yan, Zhen (American Association for the Advancement of Science, 2026-02-27)
Adenosine 5′-monophosphate–activated protein kinase (AMPK) is an energetic sensor for metabolic regulation and integration. Here, we used CRISPR-Cas9 to generate nonactivatable Ampkα knock-in (KI) mice with mutation of threonine-172 phosphorylation site to alanine (T172A), circumventing the limitations of previous genetic interventions that disrupt the protein stoichiometry. KI mice of Ampkα2, but not Ampkα1, demonstrated phenotypic changes with increased fat-to-lean mass, impaired endurance exercise capacity, and diminished mitochondrial maximal respiration and conductance in skeletal muscle. Integrated temporal multiomics analysis (proteomics/phosphoproteomics/metabolomics) in skeletal muscle at rest and during exercise establishes a pleiotropic yet imperative role of Ampkα2 T172 activation for glycolytic and oxidative metabolism, mitochondrial respiration, and contractile function. There is a substantial overlap of skeletal muscle proteomic changes in Ampkα2 T172A KI mice with that of patients with type 2 diabetes. Our findings suggest that Ampkα2 T172 activation is critical for exercise performance and energy transduction in skeletal muscle and may serve as a therapeutic target for type 2 diabetes.
A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice
Pattamaprapanont, Pattarawan; Nava, Roberto C.; Grover, Rea; Formato, Mia; Cooney, Eileen M.; Pinto, Ana Paula; Alves-Wagner, Ana B.; Das, Anamica; Guan, Yuntian; Annambhotla, Meghana; Acharya, Saanvi; Rivas, Donato A.; Lessard, Sarah J. (2025-12-01)
VO₂peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO₂peak due to an impaired adaptive response to training. Here, we show that reducing blood glucose with a carbohydrate-restricted, high fat ketogenic diet can restore aerobic exercise adaptation in male mice with hyperglycemia. Hyperglycemic mice received standard high-carbohydrate chow (CHOW), which sustains high blood glucose; or a ketogenic diet (KETO), which normalizes blood glucose levels. After aerobic exercise training, improvements in VO₂peak are blunted in CHOW, but restored by KETO. Increased VO₂peak in KETO is associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density. Moreover, KETO induces exercise-independent effects on muscle mitochondrial remodeling and substrate selection, significantly increasing fatty acid oxidation and down-regulating glucose metabolism. We identify a ketogenic diet as a potential therapy to improve aerobic exercise adaptation in the growing population with hyperglycemia.
Octopamine and tyramine dynamics predict learning rate phenotypes during associative conditioning in honey bees
Sands, Lester P.; Lei, Hong; Batten, Seth R.; Hartle, Alec; Lohrenz, Terry; Barbosa, Leonardo; Bang, Dan; Dayan, Peter; Howe, W. Matt; Smith, Brian H.; Montague, P. Read (American Association for the Advancement of Science, 2026-02-13)
Biogenic amines are fundamental for physiological homeostasis and behavioral control in both vertebrates and invertebrates. Monoamine neurotransmitters released in target brain regions conjointly regulate adaptive learning and plasticity. However, our understanding of these multianalyte mechanisms remains nascent, in part due to limitations in measurement technology. Here, during associative conditioning in honey bees, we concurrently tracked subsecond fluctuations in octopamine, tyramine, dopamine, and serotonin in the antennal lobe, where plasticity influences odorant representations. By repeatedly pairing an odorant with subsequent sucrose delivery, we observed individual differences in the conditioned response to odor, which occurred after a variable number of pairings (learners) or not at all (non-learners). The distinction between learners and non-learners was reflected in neurotransmitter responses across experimental conditions. The speed of learning, the number of pairings prior to a proboscis extension reflex, could be predicted from monoamine opponent signaling (octopamine-tyramine), from both the first presentation of the odorant alone, prior to any pairing with sucrose, and the first conditioned response to the odorant, coming after a number of sucrose pairings. These results suggest that monoamine signaling phenotypes may relate directly to the now widely reported socially relevant genetic differences in honey bee learning.
Polygenicity in a box: Copy number variants, neural circuit development, and neurodevelopmental disorders
LaMantia, Anthony-Samuel (Elsevier, 2024-12)
Clinically defined neurodevelopmental disorders (cd-NDDs), including Autistic Spectrum Disorder (ASD) and Schizophrenia (Scz), are primarily polygenic: Multiple risk genes distributed across the genome, in potentially infinite combinations, account for variable pathology. Polygenicity raises a fundamental question: Can “core” cd-NDD pathogenic mechanisms be identified given this genomic complexity? With the right models and analytic targets, a distinct class of polygenic mutations—Copy Number Variants (CNVs): contiguous gene deletions or duplications associated with cd-NDD risk—provide a singular opportunity to define cd-NDD pathology. CNVs orthologous to those that confer cd-NDD risk have been engineered in animals as well as human stem cells. Using these tools, one can determine how altered function of multiple genes cause serial stumbles over cell biological steps typically taken to build optimal “polygenic” neural circuits. Thus, cd-NDD pathology may be a consequence of polygenic deviations—stumbles—that exceed limits of adaptive variation for key developmental steps.
Impact of maternal obesity and mode of delivery on the newborn skin and oral microbiomes
Seifert, Allison; Ingram, Kelly; Eko, Embelle Ngalame; Nunziato, Jaclyn; Ahrens, Monica; Howell, Brittany R. (Microbiology Society, 2025-04-10)
Introduction. Previous studies have shown vast differences in the skin and oral microbiomes of newborns based on delivery method [Caesarean section (C-section) vs vaginal]. Exposure to or absence of certain bacteria during delivery can impact the neonate’s future susceptibility to infections, allergies or autoimmunity by altering immune functions. Few studies have focused on the impact of maternal obesity on the variations of newborn skin and oral microbiomes. Obese pregnant women typically have a higher vaginal microbiome diversity, and their pregnancies are at higher risk for adverse outcomes and complications. Hypothesis. We hypothesized that the skin and oral microbiomes of newborns born to obese mothers would include more diverse, potentially pathogenic bacteria and that the skin and oral microbiome in C-section delivered newborns would be less diverse than vaginally delivered newborns. Aim. We aim to begin to establish maternal obesity and mode of delivery as factors contributing to increased risk for negative newborn outcomes through impacts on newborn bacterial dysbiosis. Methodology. A skin swab was collected immediately following delivery of 39 newborns from 13 healthy weight body mass index (BMI 18.50–24.99), 11 overweight (BMI 25.0–29.99) and 15 obese (BMI ≥30.00) pregnant participants. An oral swab was collected immediately following delivery for 38 of these newborns from 13 healthy weight, 10 overweight and 15 obese pregnant participants. Bacterial genera were identified via 16S rRNA amplicon sequencing. Results. The newborn skin microbiome was comprised of typical skin bacteria (i.e. Corynebacterium). Newborns of obese participants had a higher relative abundance of Peptoniphilus in their skin microbiome compared to newborns of healthy weight participants (P=0.007). Neonates born via C-section had a higher relative abundance of Ureaplasma in their oral microbiome compared to neonates delivered vaginally (P=0.046). Conclusion. We identified differences in the newborn skin and oral microbiomes based on pre-pregnancy BMI and method of delivery. These differences could be linked to an increased risk of allergies, autoimmune disease and infections. Future longitudinal studies will be crucial in determining the long-term impact of these specific genera on newborn outcomes. Understanding these connections could lead to targeted interventions that reduce the risk of adverse outcomes and improve overall health trajectory.
3D-Printed Wearable Biosensors for Livestock Health Monitoring
Ali, Md. Azahar; Howell, Brittany R.; Zhang, Liqing (IEEE, 2025-07)
Livestock health monitoring stands as a linchpin in ensuring both the welfare of animals and the optimization of productivity. As we navigate toward meeting current and future food crises, the role of biosensors in this context cannot be overstated. Such biosensors serve as indispensable tools, offering real-time insights into the health status of livestock, thereby enabling early detection of diseases and prompt intervention. In addressing the challenges and potential of biosensors for livestock sensing, it is clear that while biosensors have seen extensive use in human health monitoring, their application in livestock is crucial for ensuring animal well-being and productivity, vital in meeting global food demands. To maximize effectiveness, there is a need for advanced manufacturing to develop customized, user-friendly, and cost-effective sensors. By harnessing the synergistic potential of electrochemical biosensors and advanced manufacturing, this review discusses the challenges that currently impede the widespread adoption of wearable electrochemical biosensors, advanced manufacturing techniques, and artificial intelligence in livestock sensing. This strategic approach not only bolsters animal welfare and productivity but also fortifies agricultural resilience in the face of evolving global food demands. This review highlights recent advancements in biosensors for livestock monitoring.
New focus on cardiac voltage-gated sodium channel β1 and β1B: Novel targets for treating and understanding arrhythmias?
Williams, Zachary J.; Payne, Laura Beth; Wu, Xiaobo; Gourdie, Robert G. (Elsevier, 2025-01)
Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by 2 classes of membrane-spanning subunit: an α-subunit (pore forming) and 2 β-subunits (non–pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are 4 β-subunits (β1–β4) encoded by 4 genes (SCN1B–SCN4B), each of which is expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the β-subunit extracellular amino-terminal domain facilitates adhesive interactions in intercalated discs and that its carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway, with a carboxyl-terminal peptide generated by β1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to β1, the Scn1b gene encodes for an alternative splice variant, β1B, which contains an identical extracellular adhesion domain to β1 but has a unique carboxyl-terminus. Although β1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known of the 2 β-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate β1 and β1B may be attractive targets for novel antiarrhythmic therapeutics.
Gap junctional and ephaptic coupling in cardiac electrical propagation: homocellular and heterocellular perspectives
Wu, Xiaobo; Payne, Laura Beth; Gourdie, Robert G. (Wiley, 2025-05-31)
Electrical communication in the heart is crucial for maintaining normal cardiac function. Traditionally, gap junctional coupling between cardiomyocytes has been accepted as the primary mechanism governing electrical propagation in the heart. However, numerous studies have demonstrated that gap junctions are also present between different cell types in heterocellular structures and disruption of such gap junctional coupling can be associated with cardiac dysfunction. In addition to gap junctional coupling, ephaptic coupling has been proposed as another mechanism for electrical communication between cardiomyocytes. Reducing ephaptic coupling has been shown to have negative impacts on cardiac conduction. While the existence of ephaptic coupling between different types of cardiac cell is under investigation, a recent study suggests that ephaptic coupling at heterocellular contacts between cardiomyocytes and fibroblasts may provide a proarrhythmic substrate in cardiac disease. In this review, we examine the current literature on electrical communication in the heart, including gap junctional and ephaptic coupling in homocellular and heterocellular contexts. Further, we offer a perspective on gaps in knowledge and opportunities for further advancing our understanding of electrical coupling mechanisms in action potential propagation in the heart. (Figure presented.).
Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction
Adams, William P.; Raisch, Tristan B.; Zhao, Yajun; Davalos, Rafael V.; Barrett, Sarah; King, D. Ryan; Bain, Chandra B.; Colucci-Chang, Katrina; Blair, Grace A.; Hanlon, Alexandra L.; Lozano, Alicia; Veeraraghavan, Rengasayee; Wan, Xiaoping; Deschenes, Isabelle; Smyth, James W.; Hoeker, Gregory S.; Gourdie, Robert G.; Poelzing, Steven (Lippincott Williams & Wilkins, 2023-09-29)
BACKGROUND: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces. METHODS: Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. RESULTS: CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. CONCLUSIONS: Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.
PERM1 Gene Delivery via AAV Prevents Heart Failure in a Mouse Model of Pressure Overload
Sreedevi, Karthi; Montalvo, Ryan; Doku, Abbigail; Korte, Audrey; Thomas, Rebekah; Salama, Sarah; Burrows, Steven; Yan, Zhen; Zaitsev, Alexey V.; Warren, Junco S. (2025-09-30)
Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of mortality worldwide. A hallmark of HFrEF is impaired cardiomyocyte contractility accompanied by disrupted mitochondrial bioenergetics; however, no current therapy targets both pathologies simultaneously. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is downregulated in HFrEF patients. We recently demonstrated that overexpression of PERM1 via adeno-associated virus 9 (AAV9-PERM1) enhances both cardiac contractility and mitochondrial biogenesis in C57BL/6 mice. In this study, we evaluated the therapeutic potential of AAV9-PERM1 in a pressure overload-induced mouse model of HFrEF. C57BL/6 mice were treated with either AAV9-PERM1 or control AAV9-GFP (1×1012 GC/mouse), followed by transverse aortic constriction (TAC) surgery. At 4 weeks post-TAC, control mice receiving AAV-GFP exhibited reduced left ventricular ejection fraction (LVEF), whereas AAV-PERM1 preserved LVEF at baseline levels. This cardioprotective effect was sustained through 8 weeks. Notably, AAV9-PERM1 completely abrogated TAC-induced cardiac hypertrophy and fibrosis. Mitochondrial analysis revealed that AAV9-PERM1 preserved mitochondrial DNA copy number and TFAM protein levels, both of which were reduced by TAC in control hearts. AAV9-PERM1 also improved mitochondrial respiration using pyruvate and octanoylcarnitine as substrates and prevented TAC-induced impairments in oxidative capacity. While PGC-1α expression remained unchanged in control TAC hearts, it was modestly yet significantly upregulated by AAV9-PERM1 in both sham and TAC groups. In addition, AAV9-PERM1 suppressed TACinduced increases in O-GlcNAcylation, a stress-related posttranslational modification of proteins. Coimmunoprecipitation further revealed interactions of PERM1 with creatine kinase and troponin C, key proteins in ATP transduction and contractility, suggesting a functional coupling between mitochondrial energetics and contractility. In conclusion, AAV-PERM1 gene therapy effectively preserves cardiac function under pressure overload by maintaining mitochondrial biogenesis, respiration capacity and contractility. This study further suggests AAV-PERM1 as a promising therapeutic strategy for HFrEF.
Analysis of Systolic Cardiac Function in PERM1-knockout Mice: Insights from A Retrospective Study in Large Cohorts of Animals
Zaitsev, Alexey V.; Sreedevi, Karthi; Goode, Brianna; Warren, Junco S. (Springer Nature, 2025-08-13)
Several groups demonstrated that PERM1 is a positive regulator of mitochondrial bioenergetics in the heart. However, discrepant results have emerged with regard to whether PERM1 loss-of-function affect cardiac contractility. Here we present data from a retrospective study collecting echocardiography data from all Perm1 knockout (Perm1-KO) mice and their wildtype (WT) littermates used for various molecular biological experiments in our lab between April of 2022 and September of 2023. This yielded an atypically large number of subjects per group, 84 WT mice and 88 Perm1-KO mice. We analyzed Echo-derived parameters of left ventricular (LV) systolic function. The ejection fraction (EF) was 65.43±7.13 in WT vs. 53.98±8.80 in Perm1-KO yielding p < 0.00000000000000004 using unpaired t-test. Other parameters which reached statistically significant difference between WT and Perm1-KO (at p < 0.05) included LV fractional shortening, LV diastolic and systolic diameters, LV anterior and posterior systolic wall thickness, LV posterior wall systolic thickening, stroke volume, and cardiac output. Changes caused by constitutive Perm1-KO can be conceptualized as reduced contractility partially compensated by increased LV circumference. This study provides a strong evidence that Perm1-KO causes a specific remodeling of cardiac contractility and provides retrospective power analysis which can be useful for future prospective studies.
Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism
Willoughby, Orion S.; Nichenko, Anna S.; Brisendine, Matthew H.; Amiri, Niloufar; Henry, Shelby N.; Braxton, Daniel S.; Brown, John R.; Kraft, Braeden J.; Jenkins, Kalyn S.; Addington, Adele K.; Zaitsev, Alexey V.; Burrows, Steven T.; McMillan, Ryan P.; Zhang, Haiyan; Tye, Spencer A.; Najt, Charles P.; Craige, Siobhan E.; Rhoads, Timothy W.; Warren, Junco S.; Drake, Joshua C. (Elsevier, 2025-11-24)
Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.

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