Scholarly Works, Fralin Biomedical Research Institute at VTC

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MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity
Pannoni, Katy E.; Fischer, Quentin S.; Tarannum, Renesa; Cawley, Mikel L.; Alsalman, Mayd M.; Acosta, Nicole; Ezigbo, Chisom; Gil, Daniela V.; Campbell, Logan A.; Farris, Shannon (Nature Research, 2025-02-06)
Neuronal mitochondria are diverse across cell types and subcellular compartments in order to meet unique energy demands. While mitochondria are essential for synaptic transmission and synaptic plasticity, the mechanisms regulating mitochondria to support normal synapse function are incompletely understood. The mitochondrial calcium uniporter (MCU) is proposed to couple neuronal activity to mitochondrial ATP production, which would allow neurons to rapidly adapt to changing energy demands. MCU is uniquely enriched in hippocampal CA2 distal dendrites compared to proximal dendrites, however, the functional significance of this layer-specific enrichment is not clear. Synapses onto CA2 distal dendrites readily express plasticity, unlike the plasticity-resistant synapses onto CA2 proximal dendrites, but the mechanisms underlying these different plasticity profiles are unknown. Using a CA2-specific MCU knockout (cKO) mouse, we found that MCU deletion impairs plasticity at distal dendrite synapses. However, mitochondria were more fragmented and spine head area was diminished throughout the dendritic layers of MCU cKO mice versus control mice. Fragmented mitochondria might have functional changes, such as altered ATP production, that could explain the structural and functional deficits at cKO synapses. Differences in MCU expression across cell types and circuits might be a general mechanism to tune mitochondrial function to meet distinct synaptic demands.
Circadian clock gene polymorphisms implicated in human pathologies
Janoski, Jesse R.; Aiello, Ignacio; Lundberg, Clayton W.; Finkielstein, Carla V. (Cell Press, 2024-06-12)
Circadian rhythms, ~24 h cycles of physiological and behavioral processes, can be synchronized by external signals (e.g., light) and persist even in their absence. Consequently, dysregulation of circadian rhythms adversely affects the well-being of the organism. This timekeeping system is generated and sustained by a genetically encoded endogenous mechanism composed of interlocking transcriptional/translational feedback loops that generate rhythmic expression of core clock genes. Genome-wide association studies (GWAS) and forward genetic studies show that SNPs in clock genes influence gene regulation and correlate with the risk of developing various conditions. We discuss genetic variations in core clock genes that are associated with various phenotypes, their implications for human health, and stress the need for thorough studies in this domain of circadian regulation.
Durotaxis and extracellular matrix degradation promote clustering of cancer cells
Potomkin, Mykhailo; Kim, Oleg V.; Klymenko, Yuliya; Alber, Mark; Aronson, Igor S. (Elsevier, 2025-01-24)
Early stages of metastasis depend on the collective behavior of cancer cells and their interaction 23 with the extracellular matrix (ECM). Cancer cell clusters are known to exhibit higher metastatic 24 potential than single cells. To explore clustering dynamics, we developed a calibrated computa- 25 tional model describing how motile cancer cells biochemically and biomechanically interact with 26 the ECM during the initial invasion phase, including ECM degradation and mechanical remod- 27 eling. The model reveals that cluster formation time, size, and shape are influenced by ECM 28 degradation rates and cellular responsiveness to external stresses (durotaxis). The results align 29 with experimental observations, demonstrating distinct cell trajectories and cluster morphologies 30 shaped by biomechanical parameters. These simulations provide valuable insights into cancer 31 invasion dynamics and may suggest potential therapeutic strategies targeting early-stage inva- 32 sive cells.
Reinforcement learning processes as forecasters of depression remission
Bansal, Vansh; McCurry, Katherine L.; Lisinski, Jonathan; Kim, Dong-Youl; Goyal, Shivani; Wang, John M.; Lee, Jacob; Brown, Vanessa M.; LaConte, Stephen M.; Casas, Brooks; Chiu, Pearl H. (Elsevier, 2024-09-11)
Background: Aspects of reinforcement learning have been associated with specific depression symptoms and may inform the course of depressive illness. Methods: We applied support vector machines to investigate whether blood‑oxygen-level dependent (BOLD) responses linked with neural prediction error (nPE) and neural expected value (nEV) from a probabilistic learning task could forecast depression remission. We investigated whether predictions were moderated by treatment use or symptoms. Participants included 55 individuals (n = 39 female) with a depression diagnosis at baseline; 36 of these individuals completed standard cognitive behavioral therapy and 19 were followed during naturalistic course of illness. All participants were assessed for depression diagnosis at a follow-up visit. Results: Both nPE and nEV classifiers forecasted remission significantly better than null classifiers. The nEV classifier performed significantly better than the nPE classifier. We found no main or interaction effects of treatment status on nPE or nEV accuracy. We found a significant interaction between nPE-forecasted remission status and anhedonia, but not for negative affect or anxious arousal, when controlling for nEV-forecasted remission status. Limitations: Our sample size, while comparable to that of other studies, limits options for maximizing and evaluating model performance. We addressed this with two standard methods for optimizing model performance (90:10 train and test scheme and bootstrapped sampling). Conclusions: Results support nEV and nPE as relevant biobehavioral signals for understanding depression outcome independent of treatment status, with nEV being stronger than nPE as a predictor of remission. Reinforcement learning variables may be useful components of an individualized medicine framework for depression healthcare.
Stabilizing milk-derived extracellular vesicles (mEVs) through lyophilization: a novel trehalose and tryptophan formulation for maintaining structure and Bioactivity during long-term storage
Dogan, Alan B.; Marsh, Spencer R.; Tschetter, Rachel J.; Beard, Claire E.; Amin, Md R.; Jourdan, L. Jane; Gourdie, Robert G. (2025-01-13)
Extracellular vesicles (EVs) are widely investigated for their implications in cell-cell signaling, immune modulation, disease pathogenesis, cancer, regenerative medicine, and as a potential drug delivery vector. However, maintaining integrity and bioactivity of EVs between Good Manufacturing Practice separation/filtration and end-user application remains a consistent bottleneck towards commercialization. Milk-derived extracellular vesicles (mEVs), separated from bovine milk, could provide a relatively low-cost, scalable platform for large-scale mEV production; however, the reliance on cold supply chain for storage remains a logistical and financial burden for biologics that are unstable at room temperature. Herein, we aim to characterize and engineer a freeze-dried, mEV formulation that can be stored at room temperature without sacrificing structure/bioactivity and can be reconstituted before delivery. In addition to undertaking established mEV assays of structure and function on our preparations, we introduce a novel, efficient, high throughput assay of mEV bioactivity based on Electric Cell Substrate Impedance Sensing (ECIS) in Human dermal fibroblast monolayers. By adding appropriate excipients, such as trehalose and tryptophan, we describe a protective formulation that preserves mEV bioactivity during long-term, room temperature storage. Our identification of the efficacy of tryptophan as a novel additive to mEV lyophilization solutions could represent a significant advancement in stabilizing small extracellular vesicles outside of cold storage conditions.
Emotional words evoke region- and valence-specific patterns of concurrent neuromodulator release in human thalamus and cortex
Batten, Seth R.; Hartle, Alec E.; Barbosa, Leonardo S.; Hadj-Amar, Beniamino; Bang, Dan; Melville, Natalie; Twomey, Tom; White, Jason P.; Torres, Alexis; Celaya, Xavier; McClure, Samuel M.; Brewer, Gene A.; Lohrenz, Terry; Kishida, Kenneth T.; Bina, Robert W.; Witcher, Mark R.; Vannucci, Marina; Casas, Brooks; Chiu, Pearl; Montague, P. Read; Howe, William M. (Elsevier, 2025-01-28)
Words represent a uniquely human information channel—humans use words to express thoughts and feelings and to assign emotional valence to experience. Work from model organisms suggests that valence assignments are carried out in part by the neuromodulators dopamine, serotonin, and norepinephrine. Here, we ask whether valence signaling by these neuromodulators extends to word semantics in humans by measuring sub-second neuromodulator dynamics in the thalamus (N = 13) and anterior cingulate cortex (N = 6) of individuals evaluating positive, negative, and neutrally valenced words. Our combined results suggest that valenced words modulate neuromodulator release in both the thalamus and cortex, but with regionand valence-specific response patterns, as well as hemispheric dependence for dopamine release in the anterior cingulate. Overall, these experiments provide evidence that neuromodulator-dependent valence signaling extends to word semantics in humans, but not in a simple one-valence-per-transmitter fashion.
Molecular Basis of Oncogenic PI3K Proteins
Sheng, Zhi; Beck, Patrick; Gabby, Maegan; Habte-Mariam, Semhar; Mitkos, Katherine (MDPI, 2024-12-30)
The dysregulation of phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in driving neoplastic transformation by promoting uncontrolled cell survival and proliferation. This oncogenic activity is primarily caused by mutations that are frequently found in PI3K genes and constitutively activate the PI3K signaling pathway. However, tumorigenesis can also arise from nonmutated PI3K proteins adopting unique active conformations, further complicating the understanding of PI3K-driven cancers. Recent structural studies have illuminated the functional divergence among highly homologous PI3K proteins, revealing how subtle structural alterations significantly impact their activity and contribute to tumorigenesis. In this review, we summarize current knowledge of Class I PI3K proteins and aim to unravel the complex mechanism underlying their oncogenic traits. These insights will not only enhance our understanding of PI3K-mediated oncogenesis but also pave the way for the design of novel PI3K-based therapies to combat cancers driven by this signaling pathway.
Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor
van der Heijden, Meike E.; Brown, Amanda M.; Kizek, Dominic J.; Sillitoe, Roy (eLife, 2024-07-29)
The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.
Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice
van der Heijden, Meike E. (Springer, 2024-05-23)
Evidence from clinical and preclinical studies has shown that the cerebellum contributes to cognitive functions, including social behaviors. Now that the cerebellum’s role in a wider range of behaviors has been confirmed, the question arises whether the cerebellum contributes to social behaviors via the same mechanisms with which it modulates movements. This review seeks to answer whether the cerebellum guides motor and social behaviors through identical pathways. It focuses on studies in which cerebellar cells, synapses, or genes are manipulated in a cell-type specific manner followed by testing of the effects on social and motor behaviors. These studies show that both anatomically restricted and cerebellar cortex-wide manipulations can lead to social impairments without abnormal motor control, and vice versa. These studies suggest that the cerebellum employs different cellular, synaptic, and molecular pathways for social and motor behaviors. Future studies warrant a focus on the diverging mechanisms by which the cerebellum contributes to a wide range of neural functions.
More Than a Small Brain: The Importance of Studying Neural Function during Development
Dooley, James C.; van der Heijden, Meike E. (Society for Neuroscience, 2024-11-27)
The nervous system contains complex circuits comprising thousands of cell types and trillions of connections. Here, we discuss how the field of "developmental systems neuroscience" combines the molecular and genetic perspectives of developmental neuroscience with the (typically adult-focused) functional perspective of systems neuroscience. This combination of approaches is critical to understanding how a handful of cells eventually produce the wide range of behaviors necessary for survival. Functional circuit development typically lags behind neural connectivity, leading to intermediate stages of neural activity that are either not seen in adults or, if present, are considered pathophysiological. Developmental systems neuroscience examines these intermediate stages of neural activity, mapping out the critical phases and inflection points of neural circuit function to understand how neural activity and behavior emerge across development. Beyond understanding typical development, this approach provides invaluable insight into the pathophysiology of neurodevelopmental disorders by identifying when and how functional development diverges between health and disease. We argue that developmental systems neuroscience will identify important periods of neural development, reveal novel therapeutic windows for treatment, and set the stage to answer fundamental questions about the brain in health and disease.
Gradient descent optimization of acoustic holograms for transcranial focused ultrasound
Sallam, Ahmed; Cengiz, Ceren; Pewekar, Mihir; Hoffmann, Eric; Legon, Wynn; Vlaisavljevich, Eli; Shahab, Shima (AIP Publishing, 2024-10-08)
Acoustic holographic lenses, also known as acoustic holograms, can change the phase of a transmitted wavefront in order to shape and construct complex ultrasound pressure fields, often for focusing the acoustic energy on a target region. These lenses have been proposed for transcranial focused ultrasound (tFUS) to create diffraction-limited focal zones that target specific brain regions while compensating for skull aberration. Holograms are currently designed using time-reversal approaches in full-wave time-domain numerical simulations. Such simulations need time-consuming computations, which severely limits the adoption of iterative optimization strategies. In the time-reversal method, the number and distribution of virtual sources can significantly influence the final sound field. Because of the computational constraints, predicting these effects and determining the optimal arrangement is challenging. This study introduces an efficient method for designing acoustic holograms using a volumetric holographic technique to generate focused fields inside the skull. The proposed method combines a modified mixed-domain method for ultrasonic propagation with a gradient descent iterative optimization algorithm. The findings are further validated in underwater experiments with a realistic 3D-printed skull phantom. This approach enables substantially faster holographic computation than previously reported techniques. The iterative process uses explicitly defined loss functions to bias the ultrasound field’s optimization parameters to specific desired characteristics, such as axial resolution, transversal resolution, coverage, and focal region uniformity, while eliminating the uncertainty associated with virtual sources in time-reversal techniques. The proposed techniques enable more rapid hologram computation and more flexibility in tailoring ultrasound fields for specific therapeutic requirements.
Spatial Transcriptomics and Single-Nucleus Multi-Omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development
Xu, Xiguang; Lin, Yu; Yin, Liduo; Serpa, Priscila da Silva; Conacher, Benjamin; Pacholec, Christina; Carvallo, Francisco; Hrubec, Terry; Farris, Shannon; Zimmerman, Kurt; Wang, Xiaobin; Xie, Hehuang (MDPI, 2024-11-07)
Background: Folate, an essential vitamin B9, is crucial for diverse biological processes, including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Objectives/Methods: Here, we employed a mouse model and spatial transcriptomic and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Results: Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Conclusions: Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.
Glycosphingolipids in Cardiovascular Disease: Insights from Molecular Mechanisms and Heart Failure Models
Huang, Sarah; Abutaleb, Karima; Mishra, Sumita (MDPI, 2024-10-08)
This review explores the crucial role of glycosphingolipids (GSLs) in the context of cardiovascular diseases (CVDs), focusing on their biosynthesis, metabolic pathways, and implications for clinical outcomes. GSLs are pivotal in regulating a myriad of cellular functions that are essential for heart health and disease progression. Highlighting findings from both human cohorts and animal models, this review emphasizes the potential of GSLs as biomarkers and therapeutic targets. We advocate for more detailed mechanistic studies to deepen our understanding of GSL functions in cardiovascular health, which could lead to innovative strategies for diagnosis, treatment, and personalized medicine in cardiovascular care.
Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques
Wu, Xiaobo; Meier, Linnea; Liu, Tom X.; Toldo, Stefano; Poelzing, Steven; Gourdie, Robert G. (MDPI, 2024-10-18)
Background/Objectives: The precise quantification of myocardial infarction is crucial for evaluating therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and of the isolation and quantification of diffuse fibrosis in the heart. Methods: Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Masson’s trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. Results: We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue in the four staining techniques. Notably, the infarct region on an H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise for infarct quantification. Additionally, our program can isolate and quantify diffuse fibrotic elements from an MTS-stained cardiac section, which suggests the algorithm’s potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. Conclusions: We demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as diffuse and patchy fibrosis in MTS-stained cardiac tissues.
Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes
Irwin, Rebecca M.; Thomas, Matthew A.; Fahey, Megan J.; Mayán, María D.; Smyth, James W.; Delco, Michelle L. (2024-10-10)
Background: The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) and the truncated, internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes. Methods: Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1 + and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 h in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer. Results: Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes. Conclusions Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.
The connexin 43 carboxyl terminal mimetic peptide αCT1 prompts differentiation of a collagen scar matrix in humans resembling unwounded skin
Montgomery, Jade; Richardson, William J.; Marsh, Spencer; Rhett, J. Matthew; Bustos, Francis; Degen, Katherine; Ghatnekar, Gautam S.; Grek, Christina L.; Jourdan, L. Jane; Holmes, Jeffrey W.; Gourdie, Robert G. (Wiley, 2021-07-10)
Phase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide alpha Connexin Carboxy-Terminus 1 (αCT1) improves cutaneous scar appearance by 47% 9-month postsurgery. While Cx43 and ZO-1 have been identified as molecular targets of αCT1, the mode-of-action of the peptide in scar mitigation at cellular and tissue levels remains to be further characterized. Scar histoarchitecture in αCT1 and vehicle-control treated skin wounds within the same patient were compared using biopsies from a Phase I clinical trial at 29-day postwounding. The sole effect on scar structure of a range of epidermal and dermal variables examined was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds—a characteristic that resembles unwounded skin. The with-in subject effect of αCT1 on scar collagen order observed in Phase I testing in humans was recapitulated in Sprague–Dawley rats and the IAF hairless guinea pig. Transient increase in histologic collagen density in response to αCT1 was also observed in both animal models. Mouse NIH 3T3 fibroblasts and primary human dermal fibroblasts treated with αCT1 in vitro showed more rapid closure in scratch wound assays, with individual cells showing decreased directionality in movement. An agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix postwounding that is similar to unwounded skin—changes that correlate with long-term improvement in scar appearance.
Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts
Teng, Allen C. T.; Gu, Liyang; Di Paola, Michelle; Lakin, Robert; Williams, Zachary J.; Au, Aaron; Chen, Wenliang; Callaghan, Neal; Zadeh, Farigol Hakem; Zhou, Yu-Qing; Fatah, Meena; Chatterjee, Diptendu; Jourdan, L. Jane; Liu, Jack; Simmons, Craig A.; Kislinger, Thomas; Yip, Christopher M.; Backx, Peter H.; Gourdie, Robert G.; Hamilton, Robert M.; Gramolini, Anthony O. (Nature Portfolio, 2022-10-18)
The intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigate the functional and cellular effects of Tmem65 reductions on the myocardium in a mouse model by injecting CD1 mouse pups (3–7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA, which reduces Tmem65 expression by 90% in mouse ventricles compared to scrambled shRNA injection. Tmem65 knockdown (KD) results in increased mortality which is accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection and progression to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts display depressed hemodynamics as measured echocardiographically as well as slowed conduction in optical recording accompanied by prolonged PR intervals and QRS duration in electrocardiograms. Immunoprecipitation and super-resolution microscopy demonstrate a physical interaction between Tmem65 and sodium channel β subunit (β1) in mouse hearts and this interaction appears to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na+ currents but did show reduced Ca2+ and K+ currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.
Attachment and borderline personality disorder as the dance unfolds: A quantitative analysis of a novel paradigm
Mancinelli, Federico; Nolte, Tobias; Griem, Julia; Lohrenz, Terry; Feigenbaum, Janet; Casas, Brooks; Montague, P. Read; Fonagy, Peter; Mathys, Christoph (Elsevier, 2024-04-17)
Current research on personality disorders strives to identify key behavioural and cognitive facets of patient functioning, to unravel the underlying root causes and maintenance mechanisms. This process often involves the application of social paradigms — however, these often only include momentary affective depictions rather than unfolding interactions. This constitutes a limitation in our capacity to probe core symptoms, and leaves potential findings uncovered which could help those who are in close relationships with affected individuals. Here, we deployed a novel task in which subjects interact with four unknown virtual partners in a turn-taking paradigm akin to a dance, and report on their experience with each. The virtual partners embody four combinations of low/high expressivity of positive/negative mood. Higher scores on our symptomatic measures of attachment anxiety, avoidance, and borderline personality disorder (BPD) were all linked to a general negative appraisal of all the interpersonal experiences. Moreover, the negative appraisal of the partner who displayed a high negative/low positive mood was tied with attachment anxiety and BPD symptoms. The extent to which subjects felt responsible for causing partners’ distress was most strongly linked to attachment anxiety. Finally, we provide a fully-fledged exploration of move-by-move action latencies and click distances from partners. This analysis underscored slower movement initiation from anxiously attached individuals throughout all virtual interactions. In summary, we describe a novel paradigm for second-person neuroscience, which allowed both the replication of established results and the capture of new behavioural signatures associated with attachment anxiety, and discuss its limitations.
Linking mentalizing capacity, shame, and depressive symptoms in the context of childhood maltreatment
Schwarzer, Nicola-Hans; Nolte, Tobias; Fonagy, Peter; Feigenbaum, Janet; Casas, Brooks; Rüfenacht, Eva; Gingelmaier, Stephan; Leibowitz, Judy; Pilling, Steve; Montague, P. Read (Elsevier, 2024-08-01)
Background: Experiences of childhood maltreatment have been shown to be a crucial predictor of depressive symptoms. Objective: This study investigated the association between a history of maltreatment and depressive symptoms in a mixed sample of adults, exploring whether feelings of shame and impairments in mentalizing mediate this association and potentially represent health-affecting factors associated with an increase in depressive symptoms. Further, the association between feelings of shame and depressive symptoms was expected to be moderated by impairments in mentalizing. Participants and setting: A mixed sample of 796 adults, including clinical and non-clinical participants, completed questionnaires assessing retrospectively rated experiences of childhood maltreatment, feelings of shame, mentalizing capacities, and current depressive symptoms in a cross-sectional design. Methods: The hypotheses were tested using structural equation modelling. Results: Associations were found between childhood maltreatment, feelings of shame, impairments in mentalizing, and depressive symptoms. Impairments in mentalizing and feelings of shame partially mediated the link between maltreatment and depressive symptoms. However, impairments in mentalizing did not moderate the link between shame and depressive symptoms. Conclusion: The current study provides evidence for the role of metacognitive processes that affect mental health problems in the domain of depression. Psychological treatments that promote mentalizing capacities might be helpful in reducing feelings of shame, and consequently in reducing depressive symptoms.
High-Resolution Imaging of Human Cancer Proteins Using Microprocessor Materials
Solares, Maria J.; Jonaid, G. M.; Luqiu, William Y.; Berry, Samantha; Khadela, Janki; Liang, Yanping; Evans, Madison C.; Pridham, Kevin J.; Dearnaley, William J.; Sheng, Zhi; Kelly, Deborah F. (Wiley-V C H , 2022-07-14)
Mutations in tumor suppressor genes, such as Tumor Protein 53 (TP53), are heavily implicated in aggressive cancers giving rise to gain- and loss-of-function phenotypes. While individual domains of the p53 protein have been studied extensively, structural information for full-length p53 remains incomplete. Functionalized microprocessor chips (microchips) with properties amenable to electron microscopy permitted us to visualize complete p53 assemblies for the first time. The new structures revealed p53 in an inactive dimeric state independent of DNA binding. Residues located at the protein-protein interface corresponded with modification sites in cancer-related hot spots. Changes in these regions may amplify the toxic effects of clinical mutations. Taken together, these results contribute advances in technology and imaging approaches to decode native protein models in different states of activation.

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