ABSTRACT
Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.
ABSTRACT
BACKGROUND: Substance misuse is a major public health issue and research has established attenuated reward responses to drug cues in those who misuse substances. Yet, little is known about whether the expectation of natural reinforcers engages distinct brain regions in substance misuse. METHODS: Using functional magnetic resonance imaging (fMRI), we delivered juice at expected and unexpected times to examine reward processing dysfunctions. We focused on the responses within the left dorsal striatum (DS) in individuals with high-risk substance use (HRU, n = 65), low-risk substance use (psychiatric controls, PC, n = 65), and healthy controls (HC, n = 65). Additionally, we investigated whether the dysfunction in reward processing within the left DS is correlated with other common psychiatric symptoms. Finally, we conducted a comprehensive analysis of the whole brain to investigate other non-hypothesized brain regions. RESULTS: Compared to HC, HRU displayed lower responses to juice delivery (i.e., reward) in the left DS (p <.05). The whole-brain analysis demonstrated that compared to HC, HRU displayed significantly lower responses to reward stimuli in various brain regions, including the bilateral caudate, temporal gyrus, left frontal gyrus, middle frontal gyrus, and right thalamus. LIMITATIONS: Participants were individuals with polysubstance use; therefore, we were not able to examine the effects of individual substances. CONCLUSIONS: Our findings suggest that HRU displays lower responses to reward stimuli within the left DS and other non-hypothesized brain regions. Our findings may help further elucidate reward processing dysfunctions related to substance misuse.
Subject(s)
Inpatients , Substance-Related Disorders , Humans , Brain , Reward , Substance-Related Disorders/psychology , Brain Mapping/methodsABSTRACT
Carbon-fluorine bonds in fluorinated molecules can undergo homolytic cleavage reactions when electrons are injected, and the resulting radicals combine to form network structures characterized by reduced solubility. This crosslinking chemistry suggests a new category of patterning materials that function under electron beam (e-beam) and extreme ultraviolet (EUV) lithographic conditions. Although this chemistry enables the production of 50 nm or smaller-sized features of simple fluoroalkylated polymers, it is limited by the need for relatively large amounts of irradiation energy to achieve required solubility changes. Therefore, this study was undertaken to devise a sensitivity-enhancing strategy based on a synergistic combination of radical crosslinking and hydrogen-bonding interactions between highly fluoroalkylated copolymers. An alternating copolymer was synthesized using tert-butoxystyrene and a fluoroalkylated maleimide, the former of which produces active hydrogens through catalytic acidolysis reactions. When the polymer was blended with a catalytic amount of a photoacid generator and subjected to lithographic patterning tests under e-beam and EUV irradiation, the deprotection reactions of tert-butoxy moieties proceeded at room temperature and led to a solubility decrease. We presume the small number of hydroxyl moieties produced formed an intermolecular hydrogen-bonding network, which acted synergistically with the covalent crosslinks generated by C-F bonds. When 30 nm features of copolymer thin films were fabricated by EUV lithography, sensitivity was improved by 25-34% without significant deterioration of pattern quality, especially line-edge roughness. These results demonstrate that EUV resists with improved patterning capabilities can be achieved by combining catalytic acidolysis reactions and noncatalytic crosslinking chemistry.
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There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.
Subject(s)
Phobia, Social , Adult , Adolescent , Humans , Magnetic Resonance Imaging/methods , Brain , Anxiety , Neuroimaging/methodsABSTRACT
Over the last several decades, inpatient psychiatric length of stay (LOS) has been greatly reduced to the detriment of patients. Latent variable mixture modeling, can be used to improve the quality of care for patients by identifying unobserved subgroups and optimize treatment variables, including LOS. This study had three objectives (1) to replicate the findings made by Oh et al. in a distinct sample, (2) to examine demographic differences related to inpatient treatment trajectories, and (3) to relate additional variables to each trajectory. We collected data on six key mental illness factors and information on felonies, misdemeanors, history of stopping psychiatric medication and psychotherapy, length of time in psychotherapy, and the number of therapists and psychiatrists from 489 patients at an inpatient psychiatric hospital. We derived latent mental illness scores after applying growth mixture modeling to these data. We identified three distinct trajectories of mental illness change: High-Risk, Rapid Improvement (HR-RI), Low-Risk, Partial Response (LR-PR), and High-Risk, Gradual Improvement (HR-GI). The HR-GI group was more likely to have patients who were female, Asian, younger, Yearly Income (YI) <$20,000, that spent more time in psychotherapy throughout their life, and had the longest LOS while inpatient. The LR-PR group had was more likely to be male, Hispanic/Latino and multiracial, older, YI >$500,000, have a history of misdemeanors, and this group had the shortest LOS (p < .05). These findings replicate and extend our previous findings in Oh et al. (2020a) and highlight the clinical utility of agnostically determining the treatment trajectories.
Subject(s)
Mental Disorders , Mental Health , Humans , Male , Female , Mental Disorders/therapy , Psychotherapy , Hospitalization , Time FactorsABSTRACT
BACKGROUND: Previous neuroimaging studies have investigated reward-processing dysfunction in major depressive disorder and have led to the common finding that major depressive disorder is associated with reduced reward responses within the reward circuit. Yet it is unclear whether such reward-processing dysfunction is specifically associated with the severity of depressive symptoms in major depressive disorder or is associated with common comorbidities. METHODS: We investigated reward-processing differences using a classic juice-delivery functional magnetic resonance imaging experiment to compare psychiatric patients with severe depressive symptoms (DEPs) to both psychiatric control subjects (PCs) and healthy control subjects. In this study, the DEPs (n = 108) were matched to healthy control subjects (n = 62) for demographic characteristics and to the PCs (n = 108) for demographics and comorbid psychiatric diagnoses. An a priori region of interest, the left putamen, was selected using previous studies. An exploratory whole-brain analysis was performed to explore for nonhypothesized regions. RESULTS: Relative to the PCs and healthy control subjects, the DEP group showed smaller responses to reward stimulus in the left putamen. Whole-brain exploratory analysis revealed that DEPs had significantly lower responses to reward stimulus in the bilateral dorsal striatum (putamen and caudate), middle frontal gyrus, left precentral gyrus, and middle cingulate cortex than PCs. CONCLUSIONS: Our findings suggest that DEPs may have a lesser ability to modulate behavior as a function of reward, especially in those individuals who experience the most severe depressive symptoms. In both DEPs and PCs, the severity of depressive symptoms was related to reduced reward responses in the left putamen.
Subject(s)
Depressive Disorder, Major , Humans , Depression , Inpatients , Brain , RewardABSTRACT
Investigations to evaluate the extreme ultraviolet (EUV) lithographic performance of 160 nm thick poly(methyl methacrylate) with 13.5 nm wavelength EUV light were performed using a synchrotron radiation source at Pohang Light Source-II (PLS-II). The single system enabled the determination of the sensitivity, contrast, linear absorption coefficient, critical dimension, and line edge roughness of polymer thin films through tests and measurements. The experimental findings were also compared to theoretical results and those of previously reported studies. According to the results of the dose-to-clear test and transmission measurements, the critical dimension of a line and space pattern (>50 nm) via interference lithography with 250 nm pitch grating agreed well with the results calculated using the lumped parameter model. The experimental results demonstrated that the equipment and test protocol can be used for EUV material infrastructure evaluation in academia and in industry.
ABSTRACT
BACKGROUND AND PURPOSE: The effective connectivity of neuronal networks during passive saltatory pneumotactile velocity stimulation to the glabrous hand with different velocities is still unknown. The present study investigated the effectivity connectivity elicited by saltatory pneumotactile velocity arrays placed on the glabrous hand at three velocities (5, 25, and 65 cm/second). METHODS: Dynamic causal modeling (DCM) was used on functional MRI data sampled from 20 neurotypical adults. Five brain regions, including the left primary somatosensory (SI) and motor (M1) cortices, bilateral secondary somatosensory (SII) cortices, and right cerebellar lobule VI, were used to build model space. RESULTS: Three velocities (5, 25, and 65 cm/second) of saltatory pneumotactile stimuli were processed in both serial and parallel modes within the sensorimotor networks. The medium velocity of 25 cm/second modulated forward interhemispheric connection from the contralateral SII to the ipsilateral SII. Pneumotactile stimulation at the medium velocity of 25 cm/second also influenced contralateral M1 through contralateral SI. Finally, the right cerebellar lobule VI was involved in the sensorimotor networks. CONCLUSIONS: Our DCM results suggest the coexistence of both serial and parallel processing for saltatory pneumotactile velocity stimulation. Significant contralateral M1 modulation promotes the prospect that the passive saltatory pneumotactile velocity arrays can be used to design sensorimotor rehabilitation protocols to activate M1. The effective connectivity from the right cerebellar lobule VI to other cortical regions demonstrates the cerebellum's role in the sensorimotor networks through feedforward and feedback neuronal pathways.
Subject(s)
Brain Mapping , Magnetic Resonance Imaging , Adult , Brain , Brain Mapping/methods , Humans , Magnetic Resonance Imaging/methodsABSTRACT
A highly fluorinated alternating polymer, P(RFMi-St), possessing improved thermal properties and patterning capabilities over perfluoroalkyl polymethacrylates under high energy radiation was achieved with semi-perfluorododecyl maleimide (RFMi) and styrene (St). RFMi could be synthesised efficiently via a Mitsunobu reaction condition and copolymerised with St by free radical and reversible-deactivation radical polymerisation protocols. P(RFMi-St) showed a satisfactory glass-transition temperature (108 °C) and intermolecular cross-linking behaviour under electron-beam and commercially more important extreme UV (λ = 13.5 nm) irradiation. The exposed regions lost their solubility, resulting in the successful formation of mechanically non-deteriorated negative-tone images down to 50 nm. In addition, P(RFMi-St) could be solution-processed with chemically non-damaging fluorous liquids, which enabled the polymer to be applied effectively on top of an organic semiconductor layer as a dielectric material (dielectric constant 2.7) for the organic field-effect transistor fabrication.
ABSTRACT
BACKGROUND AND OBJECTIVES: Substance use disorder (SUD) includes maladaptive patterns of substance use despite negative consequences. Previous structural neuroimaging studies showed some structural alterations in SUD, but it remains unknown whether these alterations are specifically associated with SUD or common comorbidities. This study attempts to validate the findings of structural differences between SUD, healthy controls (HC), and psychiatric controls (PC). METHODS: We used HC (N = 86) matched for demographics, and PC (N = 86) matched for demographics and psychiatric diagnoses to a group of SUD patients (N = 86). We assessed the group differences of subcortical volumes, cortical volumes, thickness, and surface areas between SUD and HC. We then analyzed the group differences between SUD and PC within regions showing differences between SUD and HC. RESULTS: SUD had smaller left nucleus accumbens, right thalamus, right hippocampus, left caudal anterior cingulate cortex (ACC) volume, and larger right caudal ACC volume, and right caudal ACC, right caudal middle frontal gyrus (MFG), and right posterior cingulate cortex (PCC) surface than HC. Increased right caudal ACC volume and right PCC surface in SUD were the only findings when compared with PC. Several areas showed thickness alterations between SUD and HC, but none survived multiple comparisons vs PC. DISCUSSION AND CONCLUSIONS: Our findings suggest that cingulate structures may be altered in SUD compared with both HC and PC. SCIENTIFIC SIGNIFICANCE: These results are among the first to indicate that some structural alterations may be SUD-specific, and highlight a cautionary note about using HC in psychiatric biomarker research. (Am J Addict 2021;30:72-79).
Subject(s)
Brain/diagnostic imaging , Gyrus Cinguli/diagnostic imaging , Substance-Related Disorders/diagnostic imaging , Adolescent , Adult , Brain/pathology , Case-Control Studies , Comorbidity , Female , Gyrus Cinguli/pathology , Hippocampus/diagnostic imaging , Hippocampus/pathology , Humans , Inpatients , Magnetic Resonance Imaging/methods , Male , Mental Disorders/diagnostic imaging , Mental Disorders/pathology , Mental Disorders/psychology , Middle Aged , Neuroimaging , Nucleus Accumbens/diagnostic imaging , Nucleus Accumbens/pathology , Organ Size , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/pathology , Substance-Related Disorders/pathology , Substance-Related Disorders/psychology , Thalamus/diagnostic imaging , Thalamus/pathology , Young AdultABSTRACT
Early discharge or reduced length of stay for inpatient psychiatric patients is related to increased readmission rates and worse clinical outcomes including increased risk for suicide. Trajectories of mental illness outcomes have been identified as an important method for predicting the optimal length of stay but the distinguishing factors that separate trajectories remain unclear. We sought to identify the distinct classes of patients who demonstrated similar trajectories of mental illness over the course of inpatient treatment, and we explore the patient characteristics associated with these mental illness trajectories. We used data (N = 3406) from an inpatient psychiatric hospital with intermediate lengths of stay. Using growth mixture modeling, latent mental illness scores were derived from six mental illness indicators: psychological flexibility, emotion regulation problems, anxiety, depression, suicidal ideation, and disability. The patients were grouped into three distinct trajectory classes: (1) High-Risk, Rapid Improvement (HR-RI); (2) Low-Risk, Gradual Improvement (LR-GI); and (3) High-Risk, Gradual Improvement (HR-GI). The HR-GI was significantly younger than the other two classes. The HR-GI had significantly more female patients than males, while the LR-GI had more male patients than females. Our findings indicated that younger females had more severe mental illness at admission and only gradual improvement during the inpatient treatment period, and they remained in treatment for longer lengths of stay, than older males.
Subject(s)
Mental Disorders , Suicide , Female , Hospitalization , Hospitals, Psychiatric , Humans , Inpatients , Male , Mental Disorders/epidemiology , Mental Disorders/therapy , Suicidal IdeationABSTRACT
Substance abuse is commonly defined as the persistence of drug use despite negative consequences. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum was associated with compulsive reward-seeking behavior despite negative effects. It remains unknown whether drug use is associated with the connectivity between the OFC and dorsal striatum in humans. We studied the resting state functional connectivity (RSFC) between the OFC, dorsal striatum, and habenula (and the whole brain in a separate analysis) in psychiatric inpatients with high (PU, problem users) and low (LU, low users) substance use. We matched PU and LU for psychiatric comorbidities. We found that PU showed higher RSFC between the left OFC and the left dorsal striatum than LU. RSFC between the habenula and both OFC and dorsal striatum was also higher in PU, which suggests the habenula may be a part of the same circuit. Finally, higher RSFC between the OFC and insula was also observed in PU. Our data shows that OFC, habenula, dorsal striatum, and insula may play an important role in PU. Furthermore, we postulate that the habenula may link the mesolimbic and cortico-striatal systems, which are altered in PU.
Subject(s)
Habenula , Substance-Related Disorders , Brain Mapping , Humans , Magnetic Resonance Imaging , Prefrontal CortexABSTRACT
BACKGROUND: Emerging literature suggests that the arousal and regulatory systems as measured by sleep-wakefulness, heart rate (HR) and heart rate variability (HRV) may be powerful objective warning signs of suicidality. However, there is no systematic literature review examining the association between objective measurements of these variables with suicide and suicidal behavior. METHODS: A web-based, systematic literature search using PubMed and EMBASE was conducted for articles that measured sleep-wakefulness and HR/HRV quantitatively in association with suicide. Search results were limited to human subjects and articles published in peer-reviewed journals in English. There were no restrictions for age, sex, settings and durations of measurements, types of mental illnesses, or comorbidity. RESULTS: Twenty-three studies were included in the current systematic review. Across the studies, consistent patterns of disturbed sleep-wakefulness such as greater sleep onset latency and lower sleep efficiency were related to suicide. In addition, higher HR and lower variance of R-R intervals was an indicator of risk of suicide. LIMITATIONS: Studies that used different equipment for sleep studies (i.e., polysomnography, electroencephalogram, actigraphy) were combined, and potential differences in their findings due to the different equipment were not considered. CONCLUSIONS: Findings provide initial evidence for consistent patterns of sleep-wakefulness and HR/HRV possibly associated with suicidality; however, more studies are needed in order to identify the precise objective variables (e.g., sleep onset latency, high-frequency HRV), as well as time-varying patterns in these variables, that are related to acute suicide risk.
Subject(s)
Suicide , Exercise , Heart Rate , Humans , Sleep , WakefulnessABSTRACT
The cortical representations of orofacial pneumotactile stimulation involve complex neuronal networks, which are still unknown. This study aims to identify the characteristics of functional connectivity (FC) evoked by three different saltatory velocities over the perioral and buccal surface of the lower face using functional magnetic resonance imaging in twenty neurotypical adults. Our results showed a velocity of 25 cm/s evoked stronger connection strength between the right dorsolateral prefrontal cortex and the right thalamus than a velocity of 5 cm/s. The decreased FC between the right secondary somatosensory cortex and right posterior parietal cortex for 5-cm/s velocity versus all three velocities delivered simultaneously ("All ON") and the increased FC between the right thalamus and bilateral secondary somatosensory cortex for 65 cm/s vs "All ON" indicated that the right secondary somatosensory cortex might play a role in the orofacial tactile perception of velocity. Our results have also shown different patterns of FC for each seed (bilateral primary and secondary somatosensory cortex) at various velocity contrasts (5 vs 25 cm/s, 5 vs 65 cm/s, and 25 vs 65 cm/s). The similarities and differences of FC among three velocities shed light on the neuronal networks encoding the orofacial tactile perception of velocity.
ABSTRACT
Previous magnetic resonance imaging studies of post-traumatic stress disorder (PTSD) have reported cortical volume alterations in the parahippocampal, anterior cingulate cortex, and temporal pole. It is unclear, however, if these cortical regions are specifically associated with PTSD or associated with common comorbidities. Here, we present the result of cortical volume differences between PTSD and healthy and psychiatric controls. In this study, healthy controls (n = 67) were matched for demographic characteristics (age, sex, race) and psychiatric controls (n = 67) were matched for demographic characteristics plus all other psychiatric diagnoses (past and current) to a group of PTSD patients (N = 67). We assessed group differences of 34 bilateral cortical structure volumes using statistically defined brain regions-of-interest from FreeSurfer between PTSD patients and healthy controls. We found 10 regions to be significantly different between PTSD and healthy controls and analyzed the group differences between PTSD and psychiatric controls within these regions. The right temporal pole volume in PTSD was found to be significantly smaller than both healthy and psychiatry controls. Our finding suggests only right temporal pole volume reduction is specifically associated with PTSD, and also highlights the need for using appropriate controls in psychiatry research.
Subject(s)
Magnetic Resonance Imaging/trends , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/psychology , Temporal Lobe/diagnostic imaging , Adult , Female , Humans , Male , Mental Disorders/diagnostic imaging , Mental Disorders/epidemiology , Mental Disorders/psychology , Stress Disorders, Post-Traumatic/epidemiology , Young AdultABSTRACT
We report the synthesis, characterization, and photopatterning of high-k inorganic nanoparticles that are covered with highly fluorinated carboxylic acid and, as a result, are solution-processable in fluorous liquids. Barium titanate (BTO) nanoparticles, 7-8 nm in diameter, were prepared under solvothermal conditions and were surface-modified with perfluoroalkyl ether-type carboxylic acid molecules via ligand-exchange reactions. Thin films with a high dielectric constant (9.27 at 1 kHz) were achieved by spin-coating homogeneous solutions of BTO nanoparticles in a fluorous solvent (HFE-7500). Additionally, electron-beam lithography and photolithography were applied to the thin films of BTO nanoparticles, yielding BTO patterns with scales of 300 nm and 5 µm, respectively. Thus, an approach for a chemically non-damaging solution process of inorganic materials for device implementation was successfully demonstrated.
ABSTRACT
BACKGROUND: Transcranial magnetic stimulation (TMS) can be paired with functional magnetic resonance imaging (fMRI) in concurrent TMS-fMRI experiments. These multimodal experiments enable causal probing of network architecture in the human brain which can complement alternative network mapping approaches. Critically, merely introducing the TMS coil into the scanner environment can sometimes produce substantial magnetic field inhomogeneities and spatial distortions which limit the utility of concurrent TMS-fMRI. METHOD AND RESULTS: We assessed the efficacy of point spread function corrected echo planar imaging (PSF-EPI) in correcting for the field inhomogeneities associated with a TMS coil at 3â¯T. In phantom and brain scans, we quantitatively compared the coil-induced distortion artifacts measured in EPI scans with and without PSF correction. We found that the application of PSF corrections to the EPI data significantly improved signal-to-noise and reduced distortions. In phantom scans with the PSF-EPI sequence, we also characterized the temporal profile of dynamic artifacts associated with TMS delivery and found that image quality remained high as long as the TMS pulse preceded the RF excitation pulses by at least 50â¯ms. Lastly, we validated the PSF-EPI sequence in human brain scans involving TMS and motor behavior as well as resting state fMRI scans. CONCLUSIONS: Our collective results demonstrate the potential benefits of PSF-EPI for concurrent TMS-fMRI when coil-related artifacts are a concern. The ability to collect high quality resting state fMRI data in the same session as the concurrent TMS-fMRI experiment offers a unique opportunity to interrogate network architecture in the human brain.
Subject(s)
Artifacts , Brain/anatomy & histology , Brain/physiology , Multimodal Imaging/methods , Neuroimaging/methods , Brain Mapping/methods , Echo-Planar Imaging/methods , Humans , Image Processing, Computer-Assisted/methods , Transcranial Magnetic Stimulation/methodsABSTRACT
In this study, we investigated the antioxidant- and immune-stimulating activities of various garlic-Cirsium setidens Nakai blends (fermented and unfermented). The levels of S-allyl cysteine increased by 2.5 times while pectolinarigenin (an anti-inflammatory compound) increased about six times (from 1.1 ± 0.04 mg/g to 6.70 ± 0.12 mg/g) after the garlic-Cirsium setidens Nakai (80:20%, respectively) blend (S4) was fermented with Leuconostoc mesenteroides KCTC 13302. The ferric reducing ability and DPPH radical scavenging activities of all the samples increased significantly after fermentation. Ethanolic extracts of the fermented samples significantly enhanced RAW 264.7 macrophage proliferation in a dose-dependent manner and induced nitric oxide production. Among the samples, S6 and S8 stimulated the highest levels of nitric oxide (NO) production. S6 significantly induced proinflammatory cytokines TNF-α and IL-1ß as well as an anti-inflammatory cytokine IL-10 relative to control. Since the resolution of an infection would require a harmonized interplay of proinflammatory factors and anti-inflammatory cytokines, consumption of S6 could be helpful in promoting health.
ABSTRACT
The patterning of organic materials on solid substrate surfaces has been demonstrated by several methods, such as photolithography, soft lithography, imprint lithography and ink-jet printing. Fluorinated polymers and solvents provide attractive material systems to develop new patterning approaches, as they are chemically orthogonal to non-fluorinated organic molecules, allowing their efficient incorporation in different devices and systems. Moreover, fluorinated polymers are soluble in hydrofluoroether solvents, benign to biomolecules, and can be properly engineered to enable efficient photolithographic patterning. In this work, we report the development of a new photolithographic process for patterning biomolecules on any kind of surfaces either by physical adsorption or covalent bonding. The photoresist is based on a fluorinated material and hydrofluoroether solvents that have minimum interactions with biomolecules and thus they can be characterized as orthogonal to the biomolecules (bio-orthogonal). In both cases, the creation of patterns with dimensions down to 2 µm was achieved. The implementation of the developed photolithographic procedure for the creation of a multi-protein microarray is demonstrated.