Scholarly Works, Fralin Biomedical Research Institute at VTC

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Regulation of craving for real-time fMRI neurofeedback based on individual classification
Kim, Dong-Youl; Lisinski, Jonathan; Caton, Matthew; Casas, Brooks; LaConte, Stephen M.; Chiu, Pearl H. (Royal Society, 2024-10-21)
In previous real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) studies on smoking craving, the focus has been on within-region activity or between-region connectivity, neglecting the potential predictive utility of broader network activity. Moreover, there is debate over the use and relative predictive power of individual-specific and group-level classifiers. This study aims to further advance rtfMRI-NF for substance use disorders by using whole-brain rtfMRI-NF to assess smoking craving-related brain patterns, evaluate the performance of group-level or individual-level classification (n = 31) and evaluate the performance of an optimized classifier across repeated NF runs. Using real-time individual-level classifiers derived from whole-brain support vector machines, we found that classification accuracy between crave and no-crave conditions and between repeated NF runs increased across repeated runs at both individual and group levels. In addition, individual-level accuracy was significantly greater than group-level accuracy, highlighting the potential increased utility of an individually trained whole-brain classifier for volitional control over brain patterns to regulate smoking craving. This study provides evidence supporting the feasibility of using whole-brain rtfMRI-NF to modulate smoking craving-related brain responses and the potential for learning individual strategies through optimization across repeated feedback runs.This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.
Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia
Gui, Gege; Ravindra, Niveditha; Hegde, Pranay S.; Andrew, Georgia; Mukherjee, Devdeep; Wong, Zoe; Auletta, Jeffery J.; El Chaer, Firas; Chen, Evan C.; Chen, Yi-Bin; Corner, Adam; Devine, Steven M.; Iyer, Sunil G.; Jimenez, Antonio Martin Jimenez; De Lima, Marcos J. G.; Litzow, Mark R.; Kebriaei, Partow; Saber, Wael; Spellman, Stephen R.; Zeger, Scott L.; Page, Kristin M.; Dillon, Laura W.; Hourigan, Christopher S. (Springernature, 2025-02-01)
Routine genetic profiling of acute myeloid leukemia (AML) at initial diagnosis has allowed subgroup specific prognostication, drug development, and clinical management strategies. The optimal approach for treatment response assessment for AML subgroups has not yet however been determined. A nationwide cohort of 257 adult patients in first remission (CR1) from AML associated with an IDH2 mutation (IDH2m) undergoing allogeneic transplant during the period 2013-2019 in the United States had rates of relapse and survival three years after transplantation of 24% and 71%, respectively. Pre-transplant clinical flow cytometry assessment was not useful in stratifying patients based on risk of post-transplant relapse or death. DNA-sequencing was performed on CR1 blood collected within 100 days before transplant. Persistent detection of IDH2m was common (51%) and associated with increased relapse and death compared to testing negative. Co-mutation at initial diagnosis with mutated NPM1 and/or FLT3-ITD was common in this cohort (41%) and use of these validated MRD markers provided superior stratification compared to IDH2m testing. Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2m in pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.
Child maltreatment and executive function development throughout adolescence and into young adulthood
Clinchard, Claudia; Casas, Brooks; Kim-Spoon, Jungmeen (Cambridge University Press, 2024-10-28)
Child maltreatment impacts approximately one in seven children in the United States, leading to adverse outcomes throughout life. Adolescence is a time period critical for the development of executive function, but there is little research examining how abuse and neglect may differently affect the developmental trajectories of executive function throughout adolescence and into young adulthood. In the current study, 167 adolescents participated at six time points from ages 14 to 20. At each time point, adolescents completed behavioral tasks measuring the three dimensions of executive function (working memory, inhibitory control, and cognitive flexibility). Neglect and abuse in early life (ages 1-13) were reported at ages 18-19. Unconditional growth curve models revealed age-related improvement in all three executive function dimensions. Conditional growth curve models tested the prospective effects of recalled neglect and abuse on the developmental trajectories of executive function. The results revealed that neglect was associated with developmental changes in working memory abilities, such that greater levels of neglect during ages 1-13 were associated with slower increases in working memory abilities across ages 14-20. These findings highlight the adverse consequences of early neglect experiences shown by delayed working memory development during adolescence into young adulthood.
An ode to fetal, infant, and toddler neuroimaging: Chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field
Pollatou, Angeliki; Filippi, Courtney A.; Aydin, Ezra; Vaughn, Kelly; Thompson, Deanne; Korom, Marta; Dufford, Alexander J.; Howell, Brittany; Zöllei, Lilla; Di Martino, Adriana; Graham, Alice; FIT’NG Group; Scheinos, Dustin; Spann, Marisa N. (Elsevier, 2022-02-07)
Fetal, infant, and toddler neuroimaging is commonly thought of as a development of modern times (last two decades). Yet, this field mobilized shortly after the discovery and implementation of MRI technology. Here, we provide a review of the parallel advancements in the fields of fetal, infant, and toddler neuroimaging, noting the shifts from clinical to research use, and the ongoing challenges in this fast-growing field. We chronicle the pioneering science of fetal, infant, and toddler neuroimaging, highlighting the early studies that set the stage for modern advances in imaging during this developmental period, and the large-scale multi-site efforts which ultimately led to the explosion of interest in the field today. Lastly, we consider the growing pains of the community and the need for an academic society that bridges expertise in developmental neuroscience, clinical science, as well as computational and biomedical engineering, to ensure special consideration of the vulnerable mother-offspring dyad (especially during pregnancy), data quality, and image processing tools that are created, rather than adapted, for the young brain.
Measurable residual mutated IDH1 before allogeneic transplant for acute myeloid leukemia
Gui, Gege; Ravindra, Niveditha; Hegde, Pranay S.; Andrew, Georgia; Mukherjee, Devdeep; Wong, Zoe; Auletta, Jeffery J.; El Chaer, Firas; Chen, Evan C.; Chen, Yi-Bin; Corner, Adam; Devine, Steven M.; Iyer, Sunil G.; 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.; Dillon, Laura W.; Hourigan, Christopher S. (Springernature, 2025-02-01)
Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. Persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT) associates with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remain incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR reporting site between 2013 and 2019. No statistically significant post-transplant differences were observed between those testing IDH1m positive (n = 53, 36%) and negative pre-transplant (overall survival (OS): p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.
A preliminary study of the physiological and perceptual effects of GLP-1 receptor agonists during alcohol consumption in people with obesity
Quddos, Fatima; Fowler, Mary; de Lima Bovo, Ana Carolina; Elbash, Zacarya; Tegge, Allison N.; Gatchalian, Kirstin M.; Kablinger, Anita S.; DiFeliceantonio, Alexandra G.; Bickel, Warren K. (Nature Research, 2025-10-15)
Any increase in alcohol use is associated with an increase in risk of illness and mortality and consequences of chronic alcohol use include cancer, hypertension, heart and liver disease, and Alcohol Use Disorder. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective anti-glycemic and weight-loss medications with a strong safety record. There is substantial preclinical evidence and mounting retrospective and prospective randomized controlled trial evidence that GLP-1RAs could be effective for reducing alcohol consumption. However, the mechanism by which GLP-1RAs reduce alcohol intake remains unclear. While medications that reduce alcohol intake such as naltrexone and acamprosate have central nervous system action, disulfiram reduces alcohol intake through peripheral mechanisms. Here, we test whether GLP-1RAs alter alcohol’s peripheral pharmacokinetics as a potential mechanism of action for their alcohol intake suppressive effects. In this pilot study, 20 (1:1) participants with obesity in the GLP-1RA or control group consumed a challenge dose of alcohol, and we measured breath alcohol (BrAC) and the subjective effects of alcohol. We observed a delayed rise in BrAC and subjective effects in the GLP-1RA group as compared to controls, that was not explained by nausea. These data provide preliminary evidence that GLP-1RAs could act through peripheral mechanisms to suppress alcohol intake.
Demonstration of chemotherapeutic-mediated changes in meningeal lymphatics in vitro, ex vivo, and in vivo
Roberts, L. Monet; Hammel, Jennifer H.; Peng, Jin; Cunningham, Jessica J.; Schumaecker, Sophia; Davis, Skylar; Azar, Francesca; Alkaid Feng, Tzu-Yu; Wang, Maosen; Rutkowski, Melanie; Munson, Jennifer M. (Nature Research, 2025-10-13)
Systemic chemotherapy often affects cells beyond the tumor, raising concerns about their impact on peripheral tissues, including the central nervous system (CNS). The meningeal lymphatics drain cerebrospinal fluid from the CNS to the deep cervical lymph nodes, assisting in immunosurveillance and linking theCNSto the periphery. They have been implicated in a number of brain-related disorders with disruption exacerbating cognitive deficits. However, in vivo, distinguishing between direct and indirect effects of systemic chemotherapy on the meningeal lymphatics remains highly challenging, making it difficult to isolate specific impact on the CNS. To address this, we present two models we have developed that allow the examination of cellular and tissue-level changes to study the effects of systemic chemotherapy on the meningeal lymphatics. Our in vitro tissue engineered model representative of a meningeal lymphatic vessel lumen shows cell disruption, while our ex vivo model culturing mouse meningeal layers probes structural changes in a controlled setting. Finally, we correlate functional outcomes with observed changes in vivo and show that systemic taxane chemotherapy leads to morphological changes in the meningeal lymphatics, a trend of reduced flow through the brain, and impaired cognition, emphasizing the need for further study of off-target impacts in the CNS and the value of multi-model approaches.
Cumulative psychosocial and health disparities in US adolescent cigarette smoking, 2002-2019
Erath, Tyler G.; Chen, Fang Fang; Desarno, Michael; Devine, Derek; Leventhal, Adam M.; Bickel, Warren K.; Higgins, Stephen T. (Oxford University Press, 2025-04-01)
Background Understanding disparities in adolescent cigarette smoking is important for effective prevention.Methods We investigated disparities in adolescent smoking based on cumulative reported psychosocial and health risk among respondents ages 12-17 years in the US National Survey of Drug Use and Health from 2002 to 2019. Multivariable regression estimated associations of cumulative risk, survey years, and their interaction predicting past-month and daily smoking. Eleven psychosocial and health variables associated with youth smoking formed composite measures of cumulative risk, categorizing risk as low (0-2), moderate (3-4), or high (>= 5). The main outcomes were weighted past-month and daily smoking by cumulative risk and time, examining prevalence and proportional change across years.Results Among 244 519 adolescents, greater cumulative risk predicted higher smoking prevalence across all outcomes. Compared with the low-risk category, past-month smoking odds (adjusted odds ratio) were 9.14 (95% confidence interval [CI] = 8.58 to 9.72) and 46.15 (95% CI = 43.38 to 49.10) times greater in the moderate-risk and high-risk categories. For daily smoking, odds were 14.11 (95% CI = 11.92 to 16.70) and 97.32 (95% CI = 83.06 to 114.03) times greater among the moderate-risk and high-risk categories. Regarding proportional change, the low-risk category exhibited the steepest decline (-85.1%) in past-month smoking from 2002-2003 to 2018-2019, followed by the moderate-risk (-79.2%) and high-risk (-65.7%) categories. Daily smoking declined more steeply among the low-risk (-96.5%) and moderate-risk (-90.5%) than high-risk category (-86.4%).Conclusions Cumulative risk is a robust predictor of adolescent smoking. Although record-setting reductions in adolescent smoking extend across risk categories, disparities favoring youth with fewer risks are evident throughout. Recognizing cumulative risk can inform the development of more targeted and effective prevention efforts.
Normative and Informational Confidence Matching
Friedemann, Maja; Bang, Dan; Yeung, Nick (American Psychological Association, 2025-03-01)
When performing tasks in a social context, individuals tend to report confidence judgments that increasingly align with those of others over time. However, the mechanisms underlying this phenomenon, termed confidence matching, are not fully understood. This study explores two potential drivers of confidence matching behavior: informational factors that cause individuals to genuinely recalibrate their private sense of confidence based on their partner's confidence; and normative factors that lead individuals to adapt the way in which they publicly express their confidence, without changing their private assessment of their own performance. To examine these influences, we conducted two experiments examining the effects of both informational and normative factors on private and public confidence. The results demonstrate that both factors can lead to confidence matching. In a setting devoid of feedback, participants matched their confidence reports with their partner's and modified their information-seeking behavior-a proxy for private confidence-accordingly, pointing toward the role of informational factors. Conversely, in a scenario in which feedback was readily available and a joint decision-making rule was enforced, participants aligned their confidence reports with their partner's but did not adjust their information-seeking behavior, hinting at normative factors influencing the public display of confidence matching. These findings highlight the flexibility and context-sensitivity of confidence, thereby underscoring the importance of factoring in social contexts and the adaptive nature of confidence when studying metacognitive processes.
Mentalizing, epistemic trust and interpersonal problems in emotion regulation: A sequential path analysis across common mental health disorders and community control samples
Kumpasoglu, Guler Beril; Saunders, Rob; Campbell, Chloe; Nolte, Tobias; Montague, P. Read; Pilling, Steve; Leibowitz, Judy; Fonagy, Peter (Elsevier, 2025-03-01)
Background: Emotion regulation is a crucial function implicated in multiple mental health disorders; understanding the mechanisms by which emotion regulation has such impact is essential. Mentalizing has been posited as a prerequisite for effective emotion regulation. The current study aims to examine the roles of epistemic trust and interpersonal problems in driving the association between mentalizing and emotion regulation, contrasting clinical and non-clinical populations. Method: A total of 652 individuals (296 clinical and 356 community control) were employed. Sequential mediation analysis was used to examine the role of epistemic stances and interpersonal problems in the mentalizing-emotion regulation link, and moderated mediation analysis was conducted to identify group differences in these pathways. Results: Ineffective mentalizing was associated with emotion dysregulation and interpersonal problems. Higher levels of epistemic credulity and mistrust were associated with ineffective mentalizing, interpersonal problems, and emotion dysregulation. Sequential mediation analysis indicated that disruptions in epistemic trust (epistemic mistrust and credulity) and interpersonal problems partially mediated the relationship between inadequate mentalizing and emotion dysregulation, with these pathways being consistent across both clinical and control groups. The pathways including epistemic trust were not significant. Limitations: The study's limitations include a simplified theoretical model, a cross-sectional design preventing causal inference, and sample recruitment methods possibly limiting generalizability. Conclusions: These findings suggest a potential mechanism connecting mentalizing, disruptions in epistemic trust, interpersonal problems, and emotion regulation, to illuminate a crucial aspect of psychological functioning. These results emphasize the significance of social-communicative aspect in clinical outcomes.
Nanotechnology for immuno-oncology
Grippin, Adam J.; Lee, DaeYong; Parkes, Eileen E.; Jiang, Wen; Kim, Betty Y. S. (Nature Portfolio, 2025-08-01)
Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.
Treatment and recovery from opioid use disorder: The role of pain severity in individuals with moderate to severe pain
Tegge, Allison N.; Ferreira, Marco A. R.; Garafola, Peter M.; Xu, Shuangshuang; Farrell, Michael; Marsden, John; Lee, Ken; Le Moigne, Anne; Gray, Frank; Bickel, Warren K. (Elsevier, 2025-09-25)
Background: Pain is a frequent comorbidity among individuals with opioid use disorder (OUD), yet its impact on treatment outcomes is unclear. This study examined associations between pain severity and OUD treatment outcomes, including abstinence, craving, retention, and psychological functioning, in participants receiving longacting buprenorphine (BUP-XR). Methods: This secondary data analysis investigates participants from a BUP-XR phase 3 program: randomized clinical trial (NCT02357901; N = 192), open-label study (NCT02510014; N = 410); and a longitudinal observational follow-up (NCT03604861; N = 350). Pain was measured using the Brief Pain Inventory (BPI) at each treatment visit. Additional measures included demographics, opioid use, participant retention, opioid withdrawal, craving, depression, and quality of life. Analyses were performed on the full sample and the subgroup of individuals with moderate-to-severe pain (BPI≥4). Results: Participants averaged 40 years old, predominantly male (67%) and White (66%). Pain decreased after starting BUP-XR, and the reduction in pain continued throughout treatment (p-values<.001). For individuals with moderate-to-severe pain, greater concurrent pain severity was associated with lower abstinence rates (odds ratios: [0.801,0.852]; p-values<.001) in two datasets. Pain was not associated with participant retention. Lastly, greater pain severity was associated with worse physical quality of life (p-values<.001) and opioid withdrawal (pvalues<. 001), and greater depression (p-values<.001) and opioid craving (p-values<.001). Collectively, these findings are well replicated across three studies. Conclusions: Pain severity is a clinically relevant predictor of opioid use and psychosocial outcomes, but not treatment retention, in patients receiving BUP-XR. Routine pain severity monitoring may provide valuable insight into patient trajectories and support more tailored treatment approaches in OUD.
Comparing efficiency of patent production between US institutions using a hybrid NIH-USPTO dataset
DiSanto, Rocco M.; Van Dyke, Mark; Barker, Michael J.; Gourdie, Robert G. (Nature Portfolio, 2023-08)
A database that links patents to NIH awards enables evaluation of key milestones along the research translation pathway.
Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat
Tasdemiroglu, Yagmur; Council-Troche, McAlister; Chen, Miao; Ledford, Benjamin; Norris, Russell A.; Poelzing, Steven; Gourdie, Robert G.; He, Jia-Qiang (American Chemical Society, 2024-04-22)
In previous research, a synthetic α-carboxyl terminus 1 (αCT1) peptide derived from connexin 43 (Cx43) and its variant (αCT11) showed beneficial effects in an ex vivo ischemia-reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, αCT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of αCT1 or αCT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo. Following tail vein administration of αCT11 (100 μM) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury (p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF%) between the control and the αCT11 groups (p > 0.05). Surprisingly, αCT11 in blood plasma collected from these rats was undetectable within ∼10 min after tail vein injection. To investigate factors that may modulate αCT11 degradation in blood, αCT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant αCT11 degradation occurred in plasma within 10 min at 22 and 37 °C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in αCT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of αCT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics.
Spontaneous Repolarization Alternans Causes VT/VF Rearrest That Is Suppressed by Preserving Gap Junctions
Laurita, Kenneth R.; Piktel, Joseph S.; Irish, Laken; Nassal, Michelle; Cheng, Aurelia; McCauley, Matthew; Pawlowski, Gary; Dennis, Adrienne T.; Suen, Yi; Almahameed, Sufian; Ziv, Ohaz; Gourdie, Robert G.; Wilson, Lance D. (Elsevier, 2024-07-01)
Background: Ventricular tachycardia (VT)/ventricular fibrillation (VF) rearrest after successful resuscitation is common, and survival is poor. A mechanism of VT/VF, as demonstrated in ex vivo studies, is when repolarization alternans becomes spatially discordant (DIS ALT), which can be enhanced by impaired gap junctions (GJs). However, in vivo spontaneous DIS ALT–induced VT/VF has never been demonstrated, and the effects of GJ on DIS ALT and VT/VF rearrest are unknown. Objectives: This study aimed to determine whether spontaneous VT/VF rearrest induced by DIS ALT occurs in vivo, and if it can be suppressed by preserving Cx43-mediated GJ coupling and/or connectivity. Methods: We used an in vivo porcine model of resuscitation from ischemia-induced cardiac arrest combined with ex vivo optical mapping in porcine left ventricular wedge preparations. Results: In vivo, DIS ALT frequently preceded VT/VF and paralleled its incidence at normal (37°C, n = 9) and mild hypothermia (33°C, n = 8) temperatures. Maintaining GJs in vivo with rotigaptide (n = 10) reduced DIS ALT and VT/VF incidence, especially during mild hypothermia, by 90% and 60%, respectively (P < 0.001; P < 0.013). Ex vivo, both rotigaptide (n = 5) and αCT11 (n = 7), a Cx43 mimetic peptide that promotes GJ connectivity, significantly reduced DIS ALT by 60% and 100%, respectively (P < 0.05; P < 0.005), and this reduction was associated with reduced intrinsic heterogeneities of action potential duration rather than changes in conduction velocity restitution. Conclusions: These results provide the strongest in vivo evidence to date suggesting a causal relationship between spontaneous DIS ALT and VT/VF in a clinically realistic scenario. Furthermore, our results suggest that preserving GJs during resuscitation can suppress VT/VF rearrest.
Development and characterization of the mode-of-action of inhibitory and agonist peptides targeting the voltage-gated sodium channel SCN1B beta-subunit
Williams, Zachary J.; Alvarez-Laviada, Anita; Hoagland, Daniel; Jourdan, L. Jane; Poelzing, Steven; Gorelik, Julia; Gourdie, Robert G. (Elsevier, 2024-09)
Cardiac arrhythmia treatment is a clinical challenge necessitating safer and more effective therapies. Recent studies have highlighted the role of the perinexus, an intercalated disc nanodomain enriched in voltage-gated sodium channels including both Nav1.5 and β1 subunits, adjacent to gap junctions. These findings offer insights into action potential conduction in the heart. A 19-amino acid SCN1B (β1/β1B) mimetic peptide, βadp1, disrupts VGSC beta subunit-mediated adhesion in cardiac perinexii, inducing arrhythmogenic changes. We aimed to explore βadp1's mechanism and develop novel SCN1B mimetic peptides affecting β1-mediated adhesion. Using patch clamp assays in neonatal rat cardiomyocytes and electric cell substrate impedance sensing (ECIS) in β1-expressing cells, we observed βadp1 maintained inhibitory effects for up to 5 h. A shorter peptide (LQLEED) based on the carboxyl-terminus of βadp1 mimicked this inhibitory effect, while dimeric peptides containing repeated LQLEED sequences paradoxically promoted intercellular adhesion over longer time courses. Moreover, we found a link between these peptides and β1-regulated intramembrane proteolysis (RIP) - a signaling pathway effecting gene transcription including that of VGSC subunits. βadp1 increased RIP continuously over 48 h, while dimeric agonists acutely boosted RIP for up to 6 h. In the presence of DAPT, an RIP inhibitor, βadp1's effects on ECIS-measured intercellular adhesion was reduced, suggesting a relationship between RIP and the peptide's inhibitory action. In conclusion, novel SCN1B (β1/β1B) mimetic peptides are reported with the potential to modulate intercellular VGSC β1-mediated adhesion, potentially through β1 RIP. These findings suggest a path towards the development of anti-arrhythmic drugs targeting the perinexus.
Acute adenoviral infection elicits an arrhythmogenic substrate prior to myocarditis
Padget, Rachel L.; Zeitz, Michael J.; Blair, Grace A.; Wu, Xiaobo; North, Michael D.; Tanenbaum, Mira T.; Stanley, Kari E.; Phillips, Chelsea M.; King, D. Ryan; Lamouille, Samy; Gourdie, Robert G.; Hoeker, Gregory S.; Swanger, Sharon A.; Poelzing, Steven; Smyth, James W. (American Heart Association, 2024-03-29)
BACKGROUND: Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate before significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species specificity, models of infection are lacking, and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse adenovirus type-3 was previously reported as cardiotropic, yet it has not been utilized to understand the mechanisms of cardiac infection and pathology. METHODS: We have developed mouse adenovirus type-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart before an appreciable immune response or gross cardiomyopathy. RESULTS: Optical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43^Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43^Ser368 are protected against mouse adenovirus type-3–induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of mouse adenovirus type-3–infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 increases phosphorylation of Cx43^Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes, indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. CONCLUSIONS: Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.
Milk extracellular vesicles: A burgeoning new presence in nutraceuticals and drug delivery
Marsh, Spencer R.; Beard, Claire E.; Gourdie, Robert G. (Wiley, 2025-05-01)
Mammalian milk, a multifaceted developmental biofluid, has attracted new attention due to its diverse constituents and their implications for health and disease. Among these constituents, extracellular vesicles (EVs) have emerged as focal points of investigation. EVs, including exosomes and small EVs, have demonstrated biological activity in preclinical studies—including reports of enhancement of cognition and neural complexity, promotion of gastrointestinal development, barrier function and microbiome richness, the bolstering of immune response, and facilitation of musculoskeletal maturation in neonates. The richness of milk as a source of EVs is noteworthy, with hundreds of milliliters (at >10¹² EVs/mL) of nanovesicles extractable from a single liter of milk (>10¹⁴ EVs/starting liter of milk). Techniques such as tangential flow filtration hold promise for scalable production, potentially extending to thousands of liters. Together with the scale and increasing sophistication of the dairy industry, the abundance of EVs in milk underscores their commercial potential in various nutraceutical applications. Beyond natural bioactivity, milk EVs (mEVs) present intriguing possibilities as orally deliverable, non-immunogenic pharmaceutical carriers, with burgeoning interest in their utilization for heart disease and cancer chemotherapy and as vectors for gene-editing modules such as CrispR. This review synthesizes current knowledge on mEV biogenesis, characterization, isolation methodologies, and cargo contents. Moreover, it delves into the therapeutic potential of mEVs, both as inherently bioactive nanovesicles and as versatile platforms for drug delivery. As efforts progress toward large-scale implementation, rigorous attention to safe, industrial-scale production and robust assay development will be pivotal in harnessing the translational promise of small EVs from milk.
Tumor-derived extracellular vesicles disrupt the blood-brain barrier endothelium following high-frequency irreversible electroporation
Murphy, Kelsey R.; Aycock, Kenneth N.; Marsh, Spencer; Hay, Alayna N.; Athanasiadi, Ilektra; Bracha, Shay; Chang, Christine; Gourdie, Robert G.; Davalos, Rafael V.; Rossmeisl, John H. Jr.; Dervisis, Nikolaos G. (Nature Portfolio, 2024-11-18)
High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation.
Interstitial fluid transport dynamics predict glioblastoma invasion and progression
Carman-Esparza, Cora M.; Stine, Caleb A.; Atay, Naciye; Kingsmore, Kathryn M.; Wang, Maosen Wang; Woodall, Ryan T.; Rockne, Russell C.; Cunningham, Jessica J.; Munson, Jennifer M. (Springer Nature, 2025-09-03)
Glioblastoma is characterized by aggressive infiltration into surrounding brain tissue, hindering complete surgical resection and contributing to poor patient outcomes. Identifying tumor-specific invasion patterns is essential for advancing our understanding of glioblastoma progression and improving surgical and radiotherapeutic strategies. Here, we leverage in vivo dynamic contrastenhanced magnetic resonance imaging (DCE-MRI) to noninvasively quantify interstitial fluid velocity, direction, and diffusion within and around glioblastomas. We introduce a novel vector-based pathline analysis to trace downstream accumulation of fluid flow originating from the tumor core, providing a spatially explicit perspective on local flow patterns. We find that localized fluid transport metrics predict glioblastoma invasion and progression, offering a new framework to non-invasively identify high-risk regions and guide targeted treatment approaches.

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