Scholarly Works, Fralin Biomedical Research Institute at VTC

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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.
Long-Term Alterations of Glucocorticoid Receptor Expression and CD4+ T Cells in Adolescent Rhesus Macaques Following Early-Life Adversity
Sanchez, Mar M.; Panagiotakopoulos, Leonidas; Hayes, Timothy; Howell, Brittany R.; Ethun, Kelly; Easley, Kirk A.; Silvestri, Guido; Carnathan, Diane G.; McCandless, Jackson; Meyer, Jerrold; Neigh, Gretchen N. (MDPI, 2025-12-05)
Child maltreatment (MALT) is a devastating form of early-life adversity (ELA) and a primary risk for mental and physical illness. It is difficult to disentangle postnatal caregiving effects from heritable factors. Here we investigated the long-term effects of maternal care using a cross-fostering design to control for biological/heritable factors on immune function and inflammation during adolescence in a translational and naturalistic macaque model of MALT. We studied the impact of MALT on the immunophenotype of peripheral blood mononuclear cells (PBMCs) and assessed glucocorticoid receptor expression and function during adolescence. MALT was associated with elevated expression of NR3C1, the gene that encodes for the glucocorticoid receptor, in PBMCs. Glucocorticoid receptor function was not altered by MALT when examined for response to dexamethasone (DEX). In addition, MALT led to a reduction in the percentage of naïve CD4⁺ T cells and an increase in the percentage of central memory (Tcm) CD4⁺ T cells. These results suggest that MALT-exposed adolescents show residual effects of MALT on CD4⁺ T cells and increased expression of NR3C1 without demonstration of increased function of the glucocorticoid receptor. Taken together, these results suggest that ELA has enduring implications for cellular glucocorticoid receptor biology and CD4⁺ T cells.
The oncolytic adenovirus Delta-24-RGD in combination with ONC201 induces a potent antitumor response in pediatric high-grade and diffuse midline glioma models
de la Nava, Daniel; Ausejo-Mauleon, Iker; Laspidea, Virginia; Gonzalez-Huarriz, Marisol; Lacalle, Andrea; Casares, Noelia; Zalacain, Marta; Marrodan, Lucia; Garcia-Moure, Marc; Ochoa, Maria C.; Tallon-Cobos, Antonio Carlos; Hernandez-Osuna, Reyes; Marco-Sanz, Javier; Dhandapani, Laasya; Hervas-Corpion, Irati; Becher, Oren J.; Nazarian, Javad; Mueller, Sabine; Phoenix, Timothy N.; van der Lugt, Jasper; Hernaez, Mikel; Guruceaga, Elizabeth; Koschmann, Carl; Venneti, Sriram; Allen, Joshua E.; Dun, Matthew D.; Fueyo, Juan; Gomez-Manzano, Candelaria; Perez-Larraya, Jaime Gallego; Patino-Garcia, Ana; Labiano, Sara; Alonso, Marta M. (Oxford University Press, 2024-03-30)
Background Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.Methods The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and gamma H2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the efficacy of the combination in vivo. The tumor immune microenvironment was evaluated using flow cytometry, RNAseq, and multiplexed immunofluorescence staining.Results The Delta-24-RGD/ONC201 combination did not affect the virus replication capability in human pHGG and DMG models in vitro. Cytotoxicity analysis showed that the combination treatment was either synergistic or additive. Mechanistically, the combination treatment increased nuclear DNA damage and maintained the metabolic perturbation and mitochondrial damage caused by each agent alone. Delta-24-RGD/ONC201 cotreatment extended the overall survival of mice implanted with human and murine pHGG and DMG cells, independent of H3 mutation status and location. Finally, combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment to a proinflammatory phenotype.Conclusions The Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone in in vitro and in vivo models by potentiating nuclear DNA damage and in turn improving the antitumor (immune) response to each agent alone. Graphical Abstract
The phenotype of recovery XI: associations of sleep quality and perceived stress with discounting and quality of life in substance use recovery
Yeh, Yu-Hua; Zheng, Michelle H.; Tegge, Allison N.; Athamneh, Liqa N.; Freitas-Lemos, Roberta; Dwyer, Candice L.; Bickel, Warren K. (Springer, 2024-06-01)
Purpose: Sleep and stress show an interdependent relationship in physiology, and both are known risk factors for relapse in substance use disorder (SUD) recovery. However, sleep and stress are often investigated independently in addiction research. In this exploratory study, the associations of sleep quality and perceived stress with delay discounting (DD), effort discounting (ED), and quality of life (QOL) were examined concomitantly to determine their role in addiction recovery. DD has been proposed as a prognostic indicator of SUD treatment response, ED is hypothesized to be relevant to the effort to overcome addiction, and QOL is an important component in addiction recovery. Method: An online sample of 118 individuals recovering from SUDs was collected through the International Quit and Recovery Registry. Exhaustive model selection, using the Bayesian Information Criterion to determine the optimal multiple linear model, was conducted to identify variables (i.e., sleep quality, perceived stress, and demographics) contributing to the total variance in DD, ED, and QOL. Results: After model selection, sleep was found to be significantly associated with DD. Stress was found to be significantly associated with psychological health, social relationships, and environment QOL. Both sleep and stress were found to be significantly associated with physical health QOL. Neither sleep nor stress was supported as an explanatory variable of ED. Conclusion: Together, these findings suggest sleep and stress contribute uniquely to the process of addiction recovery. Considering both factors when designing interventions and planning for future research is recommended.
Multiplexed smFISH reveals the spatial organization of neuropil localized mRNAs is linked to abundance
Tarannum, Renesa; Mun, Grace; Quddos, Fatima; Swanger, Sharon A.; Steward, Oswald; Farris, Shannon (Society for Neuroscience, 2025-11)
RNA localization to neuronal axons and dendrites provides spatiotemporal control over gene expression to support synapse function. Neuronal messenger RNAs (mRNAs) localize as ribonucleoprotein particles (RNPs), commonly known as RNA granules, the composition of which influences when and where proteins are made. High-throughput sequencing has revealed thousands of mRNAs that localize to the hippocampal neuropil. Whether these mRNAs are spatially organized into common RNA granules or distributed as independent mRNAs for proper delivery to synapses is debated. Here, using highly multiplexed single molecule fluorescence in situ hybridization (HiPlex smFISH) and colocalization analyses, we investigate the subcellular spatial distribution of 15 synaptic neuropil localized mRNAs in the male and female rodent hippocampus. We observed that these mRNAs are present in the neuropil as heterogeneously sized fluorescent puncta with spatial colocalization patterns that generally scale by neuropil mRNA abundance. Indeed, differentially expressed mRNAs across cell types displayed colocalization patterns that scaled by abundance, as did simulations that reproduce cell-specific differences in abundance. Thus, the probability of these mRNAs colocalizing in the neuropil is best explained by stochastic interactions based on abundance, which places constraints on the mechanisms mediating efficient transport to synapses.Significance statement RNA localization establishes compartment-specific gene expression that is critical for synapse function. Thousands of mRNAs localize to the hippocampal synaptic neuropil, however, whether mRNAs are spatially organized as similar or distinctly composed ribonucleoprotein particles for delivery to synapses is unknown. Using multiplexed smFISH to assess the spatial organization of 15 neuropil localized mRNAs, we find that these mRNAs are present in variably sized puncta suggestive of heterogeneous transcript copy number states. RNA colocalization analyses in multiple hippocampal cell types suggest that the spatial relationship of these mRNAs is best described by their abundance in the neuropil. Stochastic RNA-RNA interactions based on neuropil abundance are consistent with models indicating that global principles, such as energy minimization, influence population localization strategies.
High-Frequency Irreversible Electroporation Alters Proteomic Profiles and Tropism of Small Tumor-Derived Extracellular Vesicles to Promote Immune Cell Infiltration
Murphy, Kelsey R.; Aycock, Kenneth N.; Marsh, Spencer; Yang, Liping; Hinckley, Jonathan; Selmek, Aubrie; Gourdie, Robert G.; Bracha, Shay; Davalos, Rafael V.; Rossmeisl, John H.; Dervisis, Nikolaos G. (MDPI, 2025-11-13)
High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technique that disrupts the blood–brain barrier (BBB) in a focal and reversible manner. However, the mechanisms underlying this disruption remain poorly understood, particularly the role of small tumor-derived extracellular vesicles (sTDEVs) released from ablated tumor cells. In this study, we investigate the proteomic and functional alterations of sTDEVs released from F98 glioma and LL/2 Lewis lung carcinoma cells following H-FIRE ablation. Mass spectrometry analysis revealed 108 unique proteins in sTDEVs derived from ablative doses of H-FIRE, which are capable of disrupting the BBB in an in vitro model. Proteomic analysis of TDEVs highlights key changes in pathways related to integrin signaling, Platelet-derived growth factor receptor (PDGFR) signaling, and ubiquitination, which may underline their interactions with brain endothelial cells. These “disruptive” sTDEVs exhibit enhanced tropism for cerebral endothelial cells both in vitro and in vivo, where they persist in the brain longer than sTDEVs released after non-ablative H-FIRE doses. Notably, when introduced into a healthy Fischer rat model, disruptive sTDEVs are associated with increased recruitment of Iba1+ immune cells, suggesting a potential role in modulating post-ablation immune responses. However, despite their altered protein composition, these vesicles do not directly increase BBB permeability in vivo. This study is the first to demonstrate that electroporation-based tumor ablation significantly alters the composition and functionality of tumor-derived extracellular vesicles, potentially influencing the tumor microenvironment post-ablation. These findings have important implications for developing multimodal treatment strategies that combine H-FIRE with systemic therapies to enhance efficacy while managing the peritumoral microenvironment.
Prospective associations of prenatal stress with child behavior: Moderation by the early childhood caregiving environment
Rinne, Gabrielle R.; Podosin, Mallory; Mahrer, Nicole E.; Shalowitz, Madeleine U.; Ramey, Sharon L.; Schetter, Christine Dunkel (Cambridge University Press, 2025-05-01)
Fetal exposure to prenatal stress can increase risk for psychopathology but postnatal caregiving may offset risk. This study tests whether maternal sensitivity and the home environment during early childhood modify associations of prenatal stress with offspring behavior in a sample of 127 mother-child pairs (n = 127). Mothers reported on perceived stress during pregnancy. Maternal sensitivity was rated by coders during a parent-child free play task when children were 4 years old. One year later, mothers reported on the home environment, child internalizing and externalizing behaviors, and children completed an assessment of inhibitory control. As hypothesized, the early childhood caregiving environment modified associations of prenatal stress with child behavior. Specifically, prenatal stress was associated with more internalizing behaviors at lower levels of maternal sensitivity and in home environments that were lower in emotional support and cognitive stimulation, but not at mean or higher levels. Furthermore, prenatal stress was associated with lower inhibitory control only at lower levels of maternal sensitivity, but not at higher levels. Maternal sensitivity and an emotionally supportive and cognitively stimulating home environment in early childhood may be important factors that mitigate risk for mental health problems among children exposed to prenatal stress.
Longitudinal Associations Among Socioeconomic Status, Delay Discounting, and Substance Use in Adolescence
Peviani, Kristin M.; Clinchard, Claudia; Bickel, Warren K.; Casas, Brooks; Kim-Spoon, Jungmeen (Springer/Plenum Publishers, 2024-12-01)
It is unclear how delay discounting and substance use develop across adolescence and whether contextual factors alter their trajectories. The present study used a longitudinal design to examine whether socioeconomic status is related to developmental trajectories of delay discounting and substance use across adolescence. The sample included 167 adolescents (M age = 14 at Time 1; 53% male) and their parents who participated annually across four years. Parents reported SES at Time 1 and adolescents completed delay discounting behavioral assessments and substance use questionnaires at Times 1 to 4. Bivariate latent growth curve modeling revealed that low SES was related to steeper increases in substance use from age 14 through 17, mediated through elevated delay discounting at age 14. The findings clarify the mediating role of delay discounting in linking family economic environment to the progression of substance use.
The Influence of Ultraprocessed Food Consumption on Energy Intake in Emerging Adulthood: A Controlled Feeding Trial
Rego, Maria L. M.; Leslie, Emma; Schmall, Emily; Capra, Bailey; Hudson, Summer; Ahrens, Monica L.; Katz, Benjamin; Davy, Kevin P.; Hedrick, Valisa E.; DiFeliceantonio, Alexandra G.; Davy, Brenda M. (Wiley, 2025-11-19)
OBJECTIVE: This study examined the impact of a 2-week eucaloric diet high in ultraprocessed foods (UPF) compared to a diet without UPF (non-UPF) on ad libitum energy intake (EI) and food selection in individuals aged 18-25. METHODS: In a randomized, crossover, proof-of-concept trial, participants completed two 14-day controlled feeding periods (81% UPF vs. 0% UPF), with a 4-week washout. Diets were matched for macronutrients, fiber, added sugar, diet quality, and energy density. Following each condition, participants consumed an ad libitum buffet meal including UPF and non-UPF. Energy and food grams consumed were quantified. Statistical analyses were conducted for the full sample, late adolescents (aged 18-21), and young adults (aged 22-25). RESULTS: Twenty-seven individuals aged 22 ± 2 years (mean BMI = 24 ± 3 kg/m2) were included. Diet compliance was ~99% overall. There was no effect of diet condition on meal total kcal or grams consumed or UPF or non-UPF consumption in the full sample (all p > 0.05). In the exploratory age subgroup analysis, an interaction between diet and age was observed for total EI (p < 0.001), where total EI increased among adolescents following the UPF diet (p = 0.03, d = 0.79), but not in young adults. CONCLUSIONS: Late adolescents may be susceptible to increased EI following a UPF diet. Future trials are warranted to evaluate this possibility. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05550818.
Injury-induced connexin 43 expression regulates endothelial wound healing
Sedovy, Meghan W.; Renton, Mark C.; Roberts, Kailynn; Leng, Xinyan; Dennison, Clare L.; Toler, Caroline O.; Leaf, Melissa R.; Lampe, Paul D.; Best, Angela K.; Isakson, Brant E.; Johnstone, Scott R. (American Physiological Society, 2025-10-28)
Endothelial cell (EC) injury is a major contributing factor to vascular surgical failure. As such, understanding the mechanisms of endothelial healing is essential to the development of vascular therapeutics and procedures. Gap junctions formed by connexin 43 (Cx43) are implicated in regulating skin wound healing, but their role in endothelial healing is unknown. Secondary analysis of RNA-seq data from in vivo injured mouse aortas (GEO: GSE115618) identified significant Cx43 upregulation in EC postinjury. We developed a novel in vivo model of EC injury using mouse carotid artery ligation to test the role of Cx43. We identified that EC immediately adjacent to the wound edge upregulate Cx43 protein expression, predominantly at cell-cell junctions. We show significantly delayed EC healing in a mouse model of inducible EC-specific Cx43 deletion [EC-Cx43 knockout (KO)] at 24 h post ligation. Single-cell RNA-seq analysis of 10,829 cells from 18 h injured EC-wild type (WT) and EC-Cx43 KO carotids revealed a Cx43-associated reduction in enrichment of EC pathways associated with migration, proliferation, and ERK/MAPK signaling pathways. Finally, the importance of Cx43 phosphorylation on EC healing was tested in mice with single-point alanine mutations (phospho-null) in known phosphorylation sites that alter Cx43 channel assembly and opening. Mice containing alanine mutations at ERK phosphorylated Cx43 serines (Cx43S²⁵⁵/²⁶²/²⁷⁹/²⁸²A) have reduced healing rates similar to EC-Cx43 KO mice. These data suggest that EC injury-induced Cx43 upregulation and subsequent Cx43 gap junction-mediated cell-to-cell communication are required for normal EC migration during wound healing after vascular injury.
Airborne Acoustic Vortex End Effector-Based Contactless, Multi-Mode, Programmable Control of Object Surfing
Li, Teng; Li, Jiali; Bo, Luyu; Brooks, Michael R.; Du, Yingshan; Cai, Bowen; Pei, Zhe; Shen, Liang; Sun, Chuangchuang; Cheng, Jiangtao; Pan, Y. Albert; Tian, Zhenhua (Wiley, 2024-09-01)
Tweezers based on optical, electric, magnetic, and acoustic fields have shown great potential for contactless object manipulation. However, current tweezers designed for manipulating millimeter-sized objects such as droplets, particles, and small animals exhibit limitations in translation resolution, range, and path complexity. Here, a novel acoustic vortex tweezers system is introduced, which leverages a unique airborne acoustic vortex end effector integrated with a three-degree-of-freedom (DoF) linear motion stage, for enabling contactless, multi-mode, programmable manipulation of millimeter-sized objects. The acoustic vortex end effector utilizes a cascaded circular acoustic array, which is portable and battery-powered, to generate an acoustic vortex with a ring-shaped energy pattern. The vortex applies acoustic radiation forces to trap and spin an object at its center, simultaneously protecting this object by repelling other materials away with its high-energy ring. Moreover, The vortex tweezers system facilitates contactless, multi-mode, programmable object surfing, as demonstrated in experiments involving trapping, repelling, and spinning particles, translating particles along complex paths, guiding particles around barriers, translating and rotating droplets containing zebrafish larvae, and merging droplets. With these capabilities, It is anticipated that the tweezers system will become a valuable tool for the automated, contactless handling of droplets, particles, and bio-samples in biomedical and biochemical research. A novel acoustic vortex tweezers system is reported, which leverages a unique acoustic vortex end effector based on a portable, battery-powered, cascaded circular acoustic array. The system enables contactless, multi-mode, programmable object surfing, as demonstrated in experiments involving trapping, repelling, and spinning particles, translating particles along complex paths, guiding particles around barriers, and translating and rotating droplets containing zebrafish larvae. image
Thalamo-hippocampal pathway determines aggression and self-harm
Jung, Jane; You, In-Jee; Shin, Sora (American Association for the Advancement of Science, 2025-11-05)
Aggression and self-harm are maladaptive coping strategies that often occur in individuals with a history of early life trauma (ELT), yet their underlying neural mechanisms remain unclear. Here, we identify L-type calcium channel (LTCC)–expressing thalamic nucleus reuniens (RE) as a critical component regulating both behaviors. ELT-induced excessive LTCC activity in vesicular glutamate transporter 2 (vGlut2) RE neurons and its corresponding effects on persistent neuronal activation contribute to increasing susceptibility to aggression and self-harm. Activation of vGlut2 RE neurons projecting to ventral hippocampus (vCA1), but not medial prefrontal cortex, promotes these behaviors in control mice. Furthermore, we found that RE neurons modulate two distinct subsets of vCA1 neurons, with one projecting to the hypothalamus to drive aggression and another to the basal amygdala to mediate self-harm. Our findings uncover how LTCC functions in the RE-to- vCA1 neural pathway increase the risk of aggression and self-harm, highlighting potential therapeutic targets for mitigating destructive behaviors following early adversity.

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