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"Lee, Ho Sung"
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Optogenetic stimulation of anterior insular cortex neurons in male rats reveals causal mechanisms underlying suppression of the default mode network by the salience network
The salience network (SN) and default mode network (DMN) play a crucial role in cognitive function. The SN, anchored in the anterior insular cortex (AI), has been hypothesized to modulate DMN activity during stimulus-driven cognition. However, the causal neural mechanisms underlying changes in DMN activity and its functional connectivity with the SN are poorly understood. Here we combine feedforward optogenetic stimulation with fMRI and computational modeling to dissect the causal role of AI neurons in dynamic functional interactions between SN and DMN nodes in the male rat brain. Optogenetic stimulation of Chronos-expressing AI neurons suppressed DMN activity, and decreased AI-DMN and intra-DMN functional connectivity. Our findings demonstrate that feedforward optogenetic stimulation of AI neurons induces dynamic suppression and decoupling of the DMN and elucidates previously unknown features of rodent brain network organization. Our study advances foundational knowledge of causal mechanisms underlying dynamic cross-network interactions and brain network switching.
The salience network has been hypothesised to modulate default mode network activity during stimulus-driven cognition. Here, the authors show that in rats, stimulation of the anterior insular cortex, a key node of the salience network, suppresses the default mode network and decouples these networks, providing in vivo evidence of a causal role of the anterior insular cortex in brain network switching.
Journal Article
Metallothionein 3 Promotes Osteoblast Differentiation in C2C12 Cells via Reduction of Oxidative Stress
Metallothioneins (MTs) are intracellular cysteine-rich proteins, and their expressions are enhanced under stress conditions. MTs are recognized as having the ability to regulate redox balance in living organisms; however, their role in regulating osteoblast differentiation is still unclear. In this research, we found that the expression of MT3, one member of the MT protein family, was specifically upregulated in the differentiation process of C2C12 myoblasts treated with bone morphogenetic protein 4 (BMP4). Transfection with MT3-overexpressing plasmids in C2C12 cells enhanced their differentiation to osteoblasts, together with upregulating the protein expression of bone specific transcription factors runt-related gene 2 (Runx2), Osterix, and distal-less homeobox 5 (Dlx5). Additionally, MT3 knockdown performed the opposite. Further studies revealed that overexpression of MT3 decreased reactive oxygen species (ROS) production in C2C12 cells treated with BMP4, and MT3 silencing enhanced ROS production. Treating C2C12 cells with antioxidant N-acetylcysteine also promoted osteoblast differentiation, and upregulated Runx2/Osterix/Dlx5, while ROS generator antimycin A treatment performed the opposite. Finally, antimycin A treatment inhibited osteoblast differentiation and Runx2/Osterix/Dlx5 expression in MT3-overexpressing C2C12 cells. These findings identify the role of MT3 in osteoblast differentiation and indicate that MT3 may have interesting potential in the field of osteogenesis research.
Journal Article
Simultaneous fMRI and fast-scan cyclic voltammetry bridges evoked oxygen and neurotransmitter dynamics across spatiotemporal scales
•By modifying FSCV components, simultaneous fMRI data can be acquired with minimal imaging artifacts.•We detect and quantify evoked dopamine and/or tissue oxygen changes using FSCV during BOLD fMRI.•FSCV-fMRI is used to derive a neurotransmitter-inclusive hemodynamic response function (HRF).•Dopamine-derived HRFs can identify brain regions that encode dopamine release amplitude.
The vascular contributions of neurotransmitters to the hemodynamic response are gaining more attention in neuroimaging studies, as many neurotransmitters are vasomodulatory. To date, well-established electrochemical techniques that detect neurotransmission in high magnetic field environments are limited. Here, we propose an experimental setting enabling simultaneous fast-scan cyclic voltammetry (FSCV) and blood oxygenation level-dependent functional magnetic imaging (BOLD fMRI) to measure both local tissue oxygen and dopamine responses, and global BOLD changes, respectively. By using MR-compatible materials and the proposed data acquisition schemes, FSCV detected physiological analyte concentrations with high temporal resolution and spatial specificity inside of a 9.4 T MRI bore. We found that tissue oxygen and BOLD correlate strongly, and brain regions that encode dopamine amplitude differences can be identified via modeling simultaneously acquired dopamine FSCV and BOLD fMRI time-courses. This technique provides complementary neurochemical and hemodynamic information and expands the scope of studying the influence of local neurotransmitter release over the entire brain.
Journal Article
Distinct neurochemical influences on fMRI response polarity in the striatum
The striatum, known as the input nucleus of the basal ganglia, is extensively studied for its diverse behavioral roles. However, the relationship between its neuronal and vascular activity, vital for interpreting functional magnetic resonance imaging (fMRI) signals, has not received comprehensive examination within the striatum. Here, we demonstrate that optogenetic stimulation of dorsal striatal neurons or their afferents from various cortical and subcortical regions induces negative striatal fMRI responses in rats, manifesting as vasoconstriction. These responses occur even with heightened striatal neuronal activity, confirmed by electrophysiology and fiber-photometry. In parallel, midbrain dopaminergic neuron optogenetic modulation, coupled with electrochemical measurements, establishes a link between striatal vasodilation and dopamine release. Intriguingly, in vivo intra-striatal pharmacological manipulations during optogenetic stimulation highlight a critical role of opioidergic signaling in generating striatal vasoconstriction. This observation is substantiated by detecting striatal vasoconstriction in brain slices after synthetic opioid application. In humans, manipulations aimed at increasing striatal neuronal activity likewise elicit negative striatal fMRI responses. Our results emphasize the necessity of considering vasoactive neurotransmission alongside neuronal activity when interpreting fMRI signal.
The relationship between striatal vascular and neural activity is not fully understood. Here the authors found neuronal activity inadequately explains striatal hemodynamic polarity, challenging classic fMRI interpretations.
Journal Article
Simulated microgravity with floating environment promotes migration of non-small cell lung cancers
A migration of cancer is one of the most important factors affecting cancer therapy. Particularly, a cancer migration study in a microgravity environment has gained attention as a tool for developing cancer therapy. In this study, we evaluated the proliferation and migration of two types (adenocarcinoma A549, squamous cell carcinoma H1703) of non-small cell lung cancers (NSCLC) in a floating environment with microgravity. When we measured proliferation of two NSCLCs in the microgravity (MG) and ground-gravity (CONT), although initial cell adhesion in MG was low, a normalized proliferation rate of A549 in MG was higher than that in CONT. Wound healing results of A549 and H1703 showed rapid recovery in MG; particularly, the migration rate of A549 was faster than that of H1703 both the normal and low proliferating conditions. Gene expression results showed that the microgravity accelerated the migration of NSCLC. Both A549 and H1703 in MG highly expressed the migration-related genes MMP-2, MMP-9, TIMP-1, and TIMP-2 compared to CONT at 24 h. Furthermore, analysis of MMP-2 protein synthesis revealed weaker metastatic performance of H1703 than that of A549. Therefore, the simulated microgravity based cancer culture environment will be a potential for migration and metastasis studies of lung cancers.
Journal Article
Auditory evoked potentials and suicidal behaviors in patients with major depressive disorders
Loudness dependence of auditory evoked potentials (LDAEP) has been proposed as a biological marker of central serotonergic activity related to suicides. This study’s objective was to analyze the difference in LDAEP between depressed patients with suicide attempts (SA) and suicidal ideation (SI). It included 130 participants (45 depressed patients with SA, 49 depressed patients with SI, and 36 healthy controls) aged > 18 years who exhibited LDAEP during electroencephalography. Psychological characteristics and event-related potentials of the three groups were compared. There was no significant difference in LDAEP between major depressive disorder (MDD) patients with SA and SI (
p
= 0.59). MDD patients with SI, who attempted suicide had significantly lower LDAEP than healthy controls (
p
= 0.01 and
p
= 0.01, respectively). However, the significance disappeared when psychological characteristics were controlled. Our results suggest that LDAEP might not be possible biomarkers for suicidal behaviors in patients with MDD. Further studies to assess the biological basis of suicide and identify the underlying dimensions that mediate the relationship between the biological basis and suicidal behaviors will be needed.
Journal Article
Real‐Time, AI‐Guided Photodynamic Laparoscopy Enhances Detection in a Rabbit Model of Peritoneal Cancer Metastasis
Accurate diagnosis is essential for effective cancer treatment, particularly in peritoneal surface malignancies, where failure to detect metastatic lesions can mislead the treatment plan. This study assessed the diagnostic accuracy of staging laparoscopy using the integration of artificial intelligence (AI)‐guided photodynamic diagnosis (PDD) with the photosensitizer Phonozen, activated at 405 nm in a rabbit model. To create peritoneal carcinomatosis, VX2 cells were inoculated laparoscopically into the peritoneum of female white New Zealand rabbits. Conventional and PDD‐guided laparoscopy utilized a customized light source that emitted broad‐spectrum white light or 405‐nm blue light, respectively. The surgical procedure comprised a tripartite approach: exploration and labeling of suspected nodules under white‐light visualization, identification of additional metastatic tumors under blue‐excitation fluorescent light, and confirmatory open laparotomy to locate overlooked nodules by palpation. Our results showed that the initial experimental data from 371 nodules in 14 rabbits, comparing conventional diagnostic laparoscopy and PDD, showed increased detection sensitivity from 67% ± 1.9% (conventional) to 98% ± 0.7% (PDD) in the small‐size nodule. In the second experimental data set from 265 nodules in 10 rabbits, the addition of a real‐time AI algorithm further increased the sensitivity to 100% ± 0.0%. Combining PDD with AI enhances the detection of peritoneal cancer metastasis in staging laparoscopy. This study demonstrates the potential of combining photodynamic diagnosis (PDD) with artificial intelligence (AI) to significantly improve the detection of peritoneal metastases in a rabbit model. The PDD‐AI approach has substantial clinical implications, particularly in the early detection of peritoneal carcinomatosis, which is crucial for effective surgical planning, optimizing treatment strategies, and reducing cancer recurrence. The findings suggest that PDD‐AI could become a valuable tool in managing peritoneal surface malignancies, such as advanced gastric cancer, leading to improved patient outcomes.
Journal Article
High-power biofuel cell textiles from woven biscrolled carbon nanotube yarns
Biofuel cells that generate electricity from glucose in blood are promising for powering implantable biomedical devices. Immobilizing interconnected enzyme and redox mediator in a highly conducting, porous electrode maximizes their interaction with the electrolyte and minimizes diffusion distances for fuel and oxidant, thereby enhancing power density. Here we report that our separator-free carbon nanotube yarn biofuel cells provide an open-circuit voltage of 0.70 V, and a maximum areal power density of 2.18 mW cm
−2
that is three times higher than for previous carbon nanotube yarn biofuel cells. Biofuel cell operation in human serum provides high areal power output, as well as markedly increased lifetime (83% remained after 24 h), compared with previous unprotected biofuel cells. Our biscrolled yarn biofuel cells are woven into textiles having the mechanical robustness needed for implantation for glucose energy harvesting.
Biofuel cells can be used as power sources for implantable biomedical devices, but suffer from limited power and lifetime. Here, Kwon
et al.
fabricate biscrolled carbon nanotube yarn electrodes, and demonstrate high fuel cell performances when used for glucose energy harvesting.
Journal Article
Evaluation of dental implant with hydroxyapatite coating by laser-induced hydrothermal synthesis: in vitro and in vivo experimental study
Various surface modification techniques have been developed to improve the survival rate of dental implants. This study aimed to evaluate both in vitro and in vivo outcomes of implants coated with a nano/micro-assembled hydroxyapatite (HA) structure using a laser-induced single-step coating (LISSC) technique. Four types of implant surfaces were examined: machined surface implants (MA), sandblasted large-grit acid-etched implants (SLA), resorbable blasting media implants (RBM), and HA-coated implants (HA). In vitro analyses included surface morphology, surface hydrophilicity, and cell attachment. Twelve rabbits and two beagle dogs were used in the in vivo experiments. The implant stability quotient (ISQ) was measured immediately after placement and again at sacrifice (rabbits: 3 and 6 weeks; beagles: 12 weeks), followed by histological evaluation and quantification of bone-to-implant contact (BIC%) and bone volume (BV%). ISQ values increased from the postoperative period to 6 or 12 weeks across all implant types. In vitro, surface roughness ranked as HA > RBM > SLA > MA, while surface wettability ranked as RBM > HA > MA > SLA. No significant differences were observed in initial cell adhesion or viability among the groups. In vivo, BV ranked as MA > RBM > SLA > HA at 3 weeks, and MA > HA > RBM > SLA at 6 weeks. BIC ranked as RBM > MA > SLA > HA at 3 weeks and HA > RBM > SLA > MA at 6 weeks. HA exhibited the greatest increases in both BV and BIC from 3 to 6 weeks. In beagles, ISQ at 12 weeks was higher than baseline for both SLA and HA, with HA demonstrating superior BV compared to SLA. Within the limitations of this preclinical study, HA-coated implants produced via the LISSC method demonstrated comparable or superior biological performance relative to conventional MA, SLA, and RBM surfaces.
Journal Article