Characteristics of Patients With Intractable Obsessive-Compulsive Disorder With High/Low Responsiveness to Gamma Knife Surgery.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition that causes significant distress and social costs and often follows a chronic course with frequent relapses. Approximately 20% of patients do not respond to medication or cognitive behavioral therapy; gamma knife surgery (GKS) has been proposed as a treatment option for these patients. However, research on GKS for OCD patients is rare. METHODS: In this study, 10 patients with treatment-resistant OCD underwent GKS, and the treatment response and side effects were assessed. The improvement in patients' obsessive-compulsive symptoms was evaluated using the Yale-Brown Obsessive Compulsive Scale (YBOCS) scores following GKS. Additionally, the characteristics distinguishing the groups with favorable responses to GKS from those with less favorable responses were examined. RESULTS: GKS was well tolerated, and patients demonstrated a statistically significant reduction in YBOCS scores before and after GKS (p=0.016). Patients that responded to GKS exhibited distinct characteristics from those who did not respond. Patients who responded poorly tended to present an earlier age of onset, a longer duration of illness, more frequent hospitalizations, poorer social functioning, and a greater incidence of suicide attempts/thoughts. CONCLUSION: This study not only demonstrated that GKS is a safe and effective treatment method for intractable OCD but also revealed characteristics distinguishing patients who respond well to GKS from those who do not. These results may aid in the selection of patients for future application of GKS.

Constructing the KOR152 Korean Young Adult Brain Atlas Utilizing the State-of-the-Art Method for the Age-Specific Population.

OBJECTIVE: Spatial normalization is an essential process for comparative analyses that heavily depends on the standard brain template used. Brain morphological differences are observed in different populations due to genetic and environmental factors, causing mismatches in regions when the data are normalized to different population templates. Recent studies have indicated differences between Caucasian and East Asian populations as well as within East Asian populations, suggesting the necessity of population-specific brain templates. Thus, this study aimed to construct a Korean young adult age-specific brain template utilizing an advanced method of template construction to update the currently available Korean template. METHODS: The KOR152 template was constructed via affine and nonlinear iterative procedures based on prior studies. We compared the morphological features of different population templates (MNI152, Indian_157, and CN200). The distance and volumetric changes before and after registering the data to these templates were calculated for registration accuracy. RESULTS: The KOR152 global brain features revealed a shorter overall length than the other population templates. The registration accuracy by distance and volumetric change was significantly lower than that of the other population templates, implying that the KOR152 was more accurate than other templates for the young adult Korean population. CONCLUSION: This study provided evidence for the need for a population-specific template that may be more appropriate for structural and functional studies in Korean populations.

Correction: Digital Phenotypes for Early Detection of Internet Gaming Disorder in Adolescent Students: Explorative Data-Driven Study.

[This corrects the article DOI: 10.2196/50259.].

Hypothalamic neuronal activation in non-human primates drives naturalistic goal-directed eating behavior.

Maladaptive feeding behavior is the primary cause of modern obesity. While the causal influence of the lateral hypothalamic area (LHA) on eating behavior has been established in rodents, there is currently no primate-based evidence available on naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating using chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, predominantly for palatable food. Positron emission tomography and magnetic resonance spectroscopy validated chemogenetic activation. Resting-state functional magnetic resonance imaging revealed that the functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.

Digital Phenotypes for Early Detection of Internet Gaming Disorder in Adolescent Students: Explorative Data-Driven Study.

BACKGROUND: Limited awareness, social stigma, and access to mental health professionals hinder early detection and intervention of internet gaming disorder (IGD), which has emerged as a significant concern among young individuals. Prevalence estimates vary between 0.7% and 15.6%, and its recognition in the International Classification of Diseases, 11th Revision and Diagnostic and Statistical Manual of Mental Disorders, 5th Edition underscores its impact on academic functioning, social isolation, and mental health challenges. OBJECTIVE: This study aimed to uncover digital phenotypes for the early detection of IGD among adolescents in learning settings. By leveraging sensor data collected from student tablets, the overarching objective is to incorporate these digital indicators into daily school activities to establish these markers as a mental health screening tool, facilitating the early identification and intervention for IGD cases. METHODS: A total of 168 voluntary participants were engaged, consisting of 85 students with IGD and 83 students without IGD. There were 53% (89/168) female and 47% (79/168) male individuals, all within the age range of 13-14 years. The individual students learned their Korean literature and mathematics lessons on their personal tablets, with sensor data being automatically collected. Multiple regression with bootstrapping and multivariate ANOVA were used, prioritizing interpretability over predictability, for cross-validation purposes. RESULTS: A negative correlation between IGD Scale (IGDS) scores and learning outcomes emerged (r166=-0.15; P=.047), suggesting that higher IGDS scores were associated with lower learning outcomes. Multiple regression identified 5 key indicators linked to IGD, explaining 23% of the IGDS score variance: stroke acceleration (ß=.33; P<.001), time interval between keys (ß=-0.26; P=.01), word spacing (ß=-0.25; P<.001), deletion (ß=-0.24; P<.001), and horizontal length of strokes (ß=0.21; P=.02). Multivariate ANOVA cross-validated these findings, revealing significant differences in digital phenotypes between potential IGD and non-IGD groups. The average effect size, measured by Cohen d, across the indicators was 0.40, indicating a moderate effect. Notable distinctions included faster stroke acceleration (Cohen d=0.68; P=<.001), reduced word spacing (Cohen d=.57; P=<.001), decreased deletion behavior (Cohen d=0.33; P=.04), and longer horizontal strokes (Cohen d=0.34; P=.03) in students with potential IGD compared to their counterparts without IGD. CONCLUSIONS: The aggregated findings show a negative correlation between IGD and learning performance, highlighting the effectiveness of digital markers in detecting IGD. This underscores the importance of digital phenotyping in advancing mental health care within educational settings. As schools adopt a 1-device-per-student framework, digital phenotyping emerges as a promising early detection method for IGD. This shift could transform clinical approaches from reactive to proactive measures.

Aberrant hyperfocusing in schizophrenia indicated by elevated theta phase-gamma amplitude coupling.

OBJECTIVE: We aimed to investigate electroencephalographic (EEG) markers of aberrant hyperfocusing, a novel framework of impaired selective attention, in schizophrenia patients by using theta phase-gamma amplitude coupling (TGC). METHODS: Fifty-four schizophrenia patients and 73 healthy controls (HCs) underwent EEG recording during an auditory oddball paradigm. For the standard and target conditions, TGC was calculated using the source signals from 25 brain regions of interest (ROIs) related to attention networks and sensory processing; TGC values were then compared across groups and conditions using two-way analysis of covariance. Correlations of altered TGC with performance on the Trail Making Test Parts A and B (TMT-A/B), were explored. RESULTS: Compared to HCs, schizophrenia patients showed elevated TGC in the left inferior frontal gyrus (IFG) and superior temporal gyrus in the standard condition but not in the target condition. Correlation analyses revealed that the TGC in the left IFG was positively correlated with the TMT-A/B completion times. CONCLUSIONS: Aberrant hyperfocusing, as reflected by elevated TGC in attention-related brain regions, was related to behavioral performance on the TMT-A/B in schizophrenia patients. SIGNIFICANCE: This study suggests that TGC is a electrophysiological marker for aberrant hyperfocusing of attentional processes that may result in cognitive impairments in schizophrenia patients.

Beyond verbal fluency in the verbal fluency task: semantic clustering as a predictor of remission in individuals at clinical high risk for psychosis.

BACKGROUND: There have been conflicting reports on whether conventional verbal fluency measures can predict the prognosis of individuals at clinical high risk (CHR) for psychosis. We aimed to investigate whether verbal fluency task measures that represent semantic processing more directly than conventional measures could be more reliable predictors of later remission in CHR individuals. METHODS: We recruited CHR individuals and healthy controls to participate in a baseline verbal fluency assessment. We identified semantic clusters within the verbal fluency task responses based on cosine similarity between consecutive words, calculated from the word embedding model. Binomial logistic regression was performed to test whether average semantic cluster size and number of words produced could be predictors of remission in CHR individuals. RESULTS: Our study sample included 96 CHR individuals and 178 healthy controls. According to clinical assessment at the last follow-up, 23 CHR individuals were classified as remitters and 73 as nonremitters, including 29 individuals who converted to psychosis. The CHR remitters showed larger average and maximum semantic cluster sizes than CHR nonremitters and healthy controls. Average semantic cluster size, but not the number of words, was a significant predictor of later remission in CHR individuals. LIMITATIONS: Our sample included only native Korean speakers. CONCLUSION: A verbal fluency task measure that more specifically represents semantic processing may be a better neurocognitive predictive marker for remission in CHR individuals than conventional verbal fluency measures. Our results provide an explanation for heterogeneous reports on whether verbal fluency can predict prognosis in CHR individuals and suggest that semantic processing is a putative cognitive predictor of their prognosis.

Anti-Inflammatory Effects and Macrophage Activation Induced by Bioavailable Cinnamon Polyphenols in Mice.

SCOPE: Cinnamon is a commonly used spice and herb that is rich in polyphenols. Due to the limited bioavailability of oral polyphenols, it remains unclear to which extent they can reach cells and exert a biological effect. This study aims to investigate the impact of bioavailable cinnamon polyphenols on lipopolysaccharide (LPS)-stimulated macrophages. METHODS AND RESULTS: A polyphenol fraction is prepared from cinnamon (Cinnamomi ramulus) (CRPF) by boiling cinnamon in water and adsorbing the extract onto a hydrophobic resin. Mice are orally administered CRPF for 7 days and then subjected to three independent experiments: endotoxemia, serum collection, and macrophage isolation. Upon intraperitoneal lipopolysaccharide challenge, CRPF decreases serum levels of inflammatory cytokines, involving suppression of liver and spleen macrophages. When normal macrophages are cultured in serum obtained from CRPF-treated mice, they exhibit an anti-inflammatory phenotype. However, macrophages from CRPF-treated mice show an increased production of inflammatory cytokines when cultured in fetal bovine serum and stimulated with LPS. CONCLUSION: The study provides evidence for the presence of bioavailable cinnamon polyphenols with anti-inflammatory properties and macrophage activation. These findings suggest that cinnamon polyphenols have the potential to modulate macrophage function, which could have implications for reducing inflammation and improving immune function.

Visual modalities-based multimodal fusion for surgical phase recognition.

Surgical workflow analysis is essential to help optimize surgery by encouraging efficient communication and the use of resources. However, the performance of phase recognition is limited by the use of information related to the presence of surgical instruments. To address the problem, we propose visual modality-based multimodal fusion for surgical phase recognition to overcome the limited diversity of information such as the presence of instruments. Using the proposed methods, we extracted a visual kinematics-based index related to using instruments, such as movement and their interrelations during surgery. In addition, we improved recognition performance using an effective convolutional neural network (CNN)-based fusion method for visual features and a visual kinematics-based index (VKI). The visual kinematics-based index improves the understanding of a surgical procedure since information is related to instrument interaction. Furthermore, these indices can be extracted in any environment, such as laparoscopic surgery, and help obtain complementary information for system kinematics log errors. The proposed methodology was applied to two multimodal datasets, a virtual reality (VR) simulator-based dataset (PETRAW) and a private distal gastrectomy surgery dataset, to verify that it can help improve recognition performance in clinical environments. We also explored the influence of a visual kinematics-based index to recognize each surgical workflow by the instrument's existence and the instrument's trajectory. Through the experimental results of a distal gastrectomy video dataset, we validated the effectiveness of our proposed fusion approach in surgical phase recognition. The relatively simple yet index-incorporated fusion we propose can yield significant performance improvements over only CNN-based training and exhibits effective training results compared to fusion based on Transformers, which require a large amount of pre-trained data.

Resistin-like Molecule α and Pulmonary Vascular Remodeling: A Multi-Strain Murine Model of Antigen and Urban Ambient Particulate Matter Co-Exposure.

Pulmonary hypertension (PH) has a high mortality and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type-2- and type-17 responses in C57BL/6 mice. Here, we focused on type-2-response-related cytokines, specifically resistin-like molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild-type or RELMα-/- mice. Vascular remodeling was assessed with histology; right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were much more prominent in the C57BL/6 strain. Compared to wild-type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV IL-33-receptor were significantly increased in BALB/c wild-type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild-type or C57BL/6-RELMα-/- mice in response to antigen/PM2.5. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- mice were not different from their respective wild-type controls. The RELMα-/- animals demonstrated significantly decreased expression of RELMß and RELMγ, which makes these mice comparable to a situation where human RELMß levels would be significantly modified, as only humans have this single RELM molecule. In BALB/c mice, RELMα was a key contributor to pulmonary vascular remodeling, increase in RV weight and RV cytokine responses induced by exposure to antigen/PM2.5, highlighting the significance of the genetic background for the biological role of RELMα.

Comparative analysis of shipboard three-component magnetometer (STCM) and proton precession magnetometer (PPM) datasets in the Australian-Antarctic Ridge.

Two different types of magnetometer, the Proton Precession Magnetometer (PPM) and the Shipboard Three-Component Magnetometer (STCM), each possess its own strengths and weaknesses in their operation. The PPM can measure the total intensity of the Earth's geomagnetic field without requiring complicated post-processing and correction. However, its operation is often limited by the condition of the sea surface. In contrast, the STCM can measure three components of the Earth's field -X, Y and Z - and is not restricted by the sea condition. However, the STCM is highly sensitive to ship's viscous magnetization, which introduces significant noise into the data quality and can lead to a loss in measured geomagnetic field. The simultaneous measurements were carried out using both types of magnetometers along the same section within the Australian-Antarctic Ridge. This region experiences strong measurements of the geomagnetic field due to its proximity to the geomagnetic South Pole. We then compared the differences between the two datasets. For each dataset, we calculated a unique linear trend and subsequently removed the discrepancy between the trends. The corrected STCM data exhibited excellent agreement with the PPM data, suggesting the potential for complementary utilization of the STCM along the PPM.

Altered intrinsic cerebellar-cerebral functional connectivity is related to negative symptoms in patients with first-episode psychosis.

BACKGROUND: Negative symptoms in schizophrenia include cognitive and affective dysfunction, such as diminished expression and amotivation. Although the cerebellar posterior hemisphere and vermis are involved in cognitive and affective functioning, previous studies on the neural mechanism of negative symptoms have mostly been confined to the cerebral cortex. This study aimed to investigate whether resting-state cerebellar-cerebral functional connectivity (FC) is altered in first-episode psychosis (FEP) patients and whether this connectivity is related to negative symptoms. METHODS: Resting-state functional magnetic resonance images were obtained from 38 FEP patients and 100 healthy controls (HCs). Using the posterior hemisphere and vermis of the cerebellum as seeds, whole-brain FC was compared between FEP patients and HCs. As cerebellar-parietal cortex connectivity is associated with negative symptoms and sociocognitive dysfunctions in schizophrenia patients, its correlation with negative symptoms was explored in FEP patients. RESULTS: FEP patients showed hyperconnectivity between the cerebellum and bilateral frontal pole (FP), occipital pole, fusiform gyrus, right lingual gyrus, central opercular cortex, anterior middle temporal gyrus, precuneus, and subcallosal cortex. Hypoconnectivity was found between the cerebellum and left FP, right anterior supramarginal gyrus (aSMG), and cerebellum crus I. FC between the left crus II and right aSMG was negatively correlated with the severity of negative symptoms and diminished expression. CONCLUSIONS: Altered FC between the cerebellum and cerebral regions related to cognitive, affective, and sensory processing was found in FEP patients and was connected to negative symptoms. These results suggest that the cerebellum plays a role in the pathophysiology of negative symptoms in schizophrenia.

Generation of bioactive MSC-EVs for bone tissue regeneration by tauroursodeoxycholic acid treatment.

Extracellular vesicles (EVs) are nano-sized carriers that reflect the parent cell's information and are known to mediate cell-cell communication. In order to overcome the disadvantages of mesenchymal stem cells (MSCs) in cell therapy, such as unexpected differentiation leading to tumorization, immune rejection, and other side effects, EVs derived from MSCs (MSC-EVs) with the tissue regenerative function have been studied as new cell-free therapeutics. However, therapeutic applications of EVs require overcoming several challenges. First, the production efficiency of MSC-EVs should be increased at least as much as the quantity of them are required to their clinical application; second, MSC-EVs needs to show various functionality further, thereby increasing tissue regeneration efficiency. In this study, we treated tauroursodeoxycholic acid (TUDCA), a biological derivative known to regulate cholesterol, to MSCs and investigated whether TUDCA treatment would be able to increase EV production efficiency and tissue regenerative capacity of EVs. Indeed, it appears that TUDCA priming to MSC increases the yield of MSC-EVs >2 times by reducing the cellular cholesterol level in MSCs and increasing the exocytosis-related CAV1 expression. Interestingly, it was found that the EVs derived from TUDCA-primed MSCs (T-EV) contained higher amounts of anti-inflammatory cytokines (IL1RN, IL6, IL10, and IL11) and osteogenic proteins (ALP, RUNX2, BMP2, BMPR1, and BMPR2) than those in control MSC-EVs (C-EV). Besides, it was shown that T-EV not only regulated M1/M2 macrophages differentiation of monocytes, also effectively increased the osteogenic differentiation of MSCs as well as bone tissue regeneration in a bone defect rat model. Based on these results, it is concluded that TUDCA treatment to MSC as a new approach endows EV with high-yield production and functionality. Thus, we strongly believe T-EV would be a powerful therapeutic material for bone tissue regeneration and potentially could be expanded to other types of tissue regeneration for clinical applications.

Combinatorial Effect of Mesenchymal Stem Cells and Extracellular Vesicles in a Hydrogel on Cartilage Regeneration.

BACKGROUND: Mesenchymal stem cells (MSCs) are used for tissue regeneration due to their wide differentiation capacity and anti-inflammatory effects. Extracellular vesicles (EVs) derived from MSCs are also known for their regenerative effects as they contain nucleic acids, proteins, lipids, and cytokines similar to those of parental cells. There are several studies on the use of MSCs or EVs for tissue regeneration. However, the combinatorial effect of human MSCs (hMSCs) and EVs is not clear. In this study, we investigated the combinatorial effect of hMSCs and EVs on cartilage regeneration via co-encapsulation in a hyaluronic-acid (HA)-based hydrogel. METHODS: A methacrylic-acid-based HA hydrogel was prepared to encapsulate hMSCs and EVs in hydrogels. Through in vitro and in vivo analyses, we investigated the chondrogenic potential of the HA hydrogel-encapsulated with hMSCs and EVs. RESULTS: Co-encapsulation of hMSCs with EVs in the HA hydrogel increased the chondrogenic differentiation of hMSCs and regeneration of damaged cartilage tissue compared with that of the HA hydrogel loaded with hMSCs only. CONCLUSION: Co-encapsulation of hMSCs and EVs in the HA hydrogel effectively enhances cartilage tissue regeneration due to the combinatorial therapeutic effect of hMSCs and EVs. Thus, in addition to cartilage tissue regeneration for the treatment of osteoarthritis, this approach would be a useful strategy to improve other types of tissue regeneration.

Immobilized Amyloid Hexamer Fragments to Map Active Sites of Amyloid-Targeting Chemicals.

As amyloid-ß (Aß) peptide is considered a biomarker and pathological culprit of Alzheimer's disease, Aß-targeting compounds have been investigated for diagnostics development and drug discovery of the disorder. Unlike amyloid plaque targeting agents, such as clinically available amyloid radiotracers intercalating into the ß-sheet structures of the aggregates, monomer and oligomer targeting chemicals are difficult to develop, as the transient and polymorphic nature of these peptides impedes their structural understanding. Here, we report a mapping approach to explore targeting residues of Aß-imaging probes and Aß-regulating drug candidates by utilizing a set of fragmented Aß hexamers immobilized on a 96-well microplate in combination with fluorescent full-length Aß for on-plate aggregation. To evaluate the mapping potential of the peptide plate, we tested previously reported fluorescent imaging agents (CRANAD-28, bis-ANS), aggregation inhibitors (curcumin, scyllo-inositol), and aggregate dissociators (necrostatin-1, sunitinib) targeting Aß. Our approach enabled mechanistic understanding of compounds targeting nonfibrillar Aß on an interacting sequence level.

Determination of the Unilaterally Damaged Region May Depend on the Asymmetry of Carotid Blood Flow Velocity in Hemiparkinsonian Monkey: A Pilot Study.

The hemiparkinsonian nonhuman primate model induced by unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the carotid artery is used to study Parkinson's disease. However, there have been no studies that the contralateral distribution of MPTP via the cerebral collateral circulation is provided by both the circle of Willis (CoW) and connections of the carotid artery. To investigate whether MPTP-induced unilaterally damaged regions were determined by asymmetrical cerebral blood flow, the differential asymmetric damage of striatal subregions, and examined structural asymmetries in a circle of Willis, and blood flow velocity of the common carotid artery were observed in three monkeys that were infused with MPTP through the left internal carotid artery. Lower flow velocity in the ipsilateral common carotid artery and a higher ratio of ipsilateral middle cerebral artery diameter to anterior cerebral artery diameter resulted in unilateral damage. Additionally, the unilateral damaged monkey observed the apomorphine-induced contralateral rotation behavior and the temporary increase of plasma RANTES. Contrastively, higher flow velocity in the ipsilateral common carotid artery was observed in the bilateral damaged monkey. It is suggested that asymmetry of blood flow velocity and structural asymmetry of the circle of Willis should be taken into consideration when establishing more efficient hemiparkinsonian nonhuman primate models.

Screening of glycosylase activity on oxidative derivatives of methylcytosine: Pedobacter heparinus SMUG2 as a formylcytosine- and carboxylcytosine-DNA glycosylase.

5-Methylcytosine (mC) is an epigenetic mark that impacts transcription, development, diseases including cancer and aging. The demethylation process involves Tet-mediated stepwise oxidation of mC to hmC, fC, or caC, excision of fC or caC by thymine-DNA glycosylase (TDG), and subsequent base excision repair. Thymine-DNA glycosylase (TDG) belongs to uracil-DNA glycosylase (UDG) superfamily, which is a group of enzymes that are initially found to be responsible for excising the deaminated bases from DNA and generating apurinic/apyrimidinic (AP) sites. mC oxidative derivatives may also be generated from Fenton chemistry and γ-irradiation. In screening DNA glycosylase activity in UDG superfamily, we identified new activity on fC- and caC-containing DNA in family 2 MUG/TDG and family 6 HDG enzymes. Surprisingly, we found a glycosylase SMUG2 from bacterium Pedobacter heparinus (Phe), a subfamily of family 3 SMUG1 DNA glycosylase, displayed catalytic activity towards not only DNA containing uracil, but also fC and caC. Given the sequence and structural differences between the family 3 and other family enzymes, we investigated the catalytic mechanism using mutational, enzyme kinetics and molecular modeling approaches. Mutational analysis and kinetics measurements identified I62, N63 and F76 of motif 1, and H205 of motif 2 in Phe SMUG2 as important catalytic residues, of which H205 of motif 2 played a critical role in catalyzing the removal of fC and caC. A catalytic model underlying the roles of these residues was proposed. The structural and catalytic differences between Phe SMUG2 and human TDG were compared by molecular modeling and molecular dynamics simulations. This study expands our understanding of DNA glycosylase capacity in UDG superfamily and provides insights into the molecular mechanism of fC and caC excision in Phe SMUG2.

DNA damage, DNA repair and carcinogenicity: Tobacco smoke versus electronic cigarette aerosol.

The allure of tobacco smoking is linked to the instant gratification provided by inhaled nicotine. Unfortunately, tobacco curing and burning generates many mutagens including more than 70 carcinogens. There are two types of mutagens and carcinogens in tobacco smoke (TS): direct DNA damaging carcinogens and procarcinogens, which require metabolic activation to become DNA damaging. Recent studies provide three new insights on TS-induced DNA damage. First, two major types of TS DNA damage are induced by direct carcinogen aldehydes, cyclic-1,N2-hydroxy-deoxyguanosine (γ-OH-PdG) and α-methyl-1, N2-γ-OH-PdG, rather than by the procarcinogens, polycyclic aromatic hydrocarbons and aromatic amines. Second, TS reduces DNA repair proteins and activity levels. TS aldehydes also prevent procarcinogen activation. Based on these findings, we propose that aldehydes are major sources of TS induce DNA damage and a driving force for carcinogenesis. E-cigarettes (E-cigs) are designed to deliver nicotine in an aerosol state, without burning tobacco. E-cigarette aerosols (ECAs) contain nicotine, propylene glycol and vegetable glycerin. ECAs induce O6-methyl-deoxyguanosines (O6-medG) and cyclic γ-hydroxy-1,N2--propano-dG (γ-OH-PdG) in mouse lung, heart and bladder tissues and causes a reduction of DNA repair proteins and activity in lungs. Nicotine and nicotine-derived nitrosamine ketone (NNK) induce the same types of DNA adducts and cause DNA repair inhibition in human cells. After long-term exposure, ECAs induce lung adenocarcinoma and bladder urothelial hyperplasia in mice. We propose that E-cig nicotine can be nitrosated in mouse and human cells becoming nitrosamines, thereby causing two carcinogenic effects, induction of DNA damage and inhibition of DNA repair, and that ECA is carcinogenic in mice. Thus, this article reviews the newest literature on DNA adducts and DNA repair inhibition induced by nicotine and ECAs in mice and cultured human cells, and provides insights into ECA carcinogenicity in mice.

Longitudinal Impact of WTC Dust Inhalation on Rat Cardiac Tissue Transcriptomic Profiles.

First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.

Triple-Network Dysconnectivity in Patients With First-Episode Psychosis and Individuals at Clinical High Risk for Psychosis.

OBJECTIVE: In the triple-network model, the salience network (SN) plays a crucial role in switching between the default-mode network (DMN) and the central executive network (CEN). Aberrant patterns of triple-network connectivity have been reported in schizophrenia patients, while findings have been less consistent for patients in the early stages of psychotic disorders. Thus, the present study examined the connectivity among the SN, DMN, and CEN in first-episode psychosis (FEP) patients and individuals at clinical high risk (CHR) for psychosis. METHODS: Thirty-nine patients with FEP, 78 patients with CHR for psychosis, and 110 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. We compared the SN, DMN, and CEN connectivity patterns of the three groups. The role of the SN in networks with significant connectivity differences was examined by mediation analysis. RESULTS: FEP patients showed lower SN-DMN and SN-CEN (cluster-level F=5.83, false discovery rate [FDR] corrected-p=0.001) connectivity than HCs. There was lower SN-DMN connectivity (cluster-level F=3.06, FDR corrected-p=0.053) at a trend level in CHR subjects compared to HCs. Between HCs and FEP patients, mediation analysis showed that SN-DMN connectivity was a mediator between group and SN-CEN connectivity. Additionally, SN-CEN connectivity functioned as a mediator between group and SN-DMN connectivity. CONCLUSION: Aberrant connectivity between the SN and DMN/CEN suggests disrupted network switching in FEP patients, although CHR subjects showed trend-level SN-DMN dysconnectivity. Our findings suggest that dysfunctional triple-network dynamics centered on the SN can appear in patients in the early stages of psychotic disorders.