Inferring delays in partially observed gene regulation processes.

MOTIVATION: Cell function is regulated by gene regulatory networks (GRNs) defined by protein-mediated interaction between constituent genes. Despite advances in experimental techniques, we can still measure only a fraction of the processes that govern GRN dynamics. To infer the properties of GRNs using partial observation, unobserved sequential processes can be replaced with distributed time delays, yielding non-Markovian models. Inference methods based on the resulting model suffer from the curse of dimensionality. RESULTS: We develop a simulation-based Bayesian MCMC method employing an approximate likelihood for the efficient and accurate inference of GRN parameters when only some of their products are observed. We illustrate our approach using a two-step activation model: an activation signal leads to the accumulation of an unobserved regulatory protein, which triggers the expression of observed fluorescent proteins. With prior information about observed fluorescent protein synthesis, our method successfully infers the dynamics of the unobserved regulatory protein. We can estimate the delay and kinetic parameters characterizing target regulation including transcription, translation, and target searching of an unobserved protein from experimental measurements of the products of its target gene. Our method is scalable and can be used to analyze non-Markovian models with hidden components. AVAILABILITY AND IMPLEMENTATION: Our code is implemented in R and is freely available with a simple example data at https://github.com/Mathbiomed/SimMCMC.

Novel Amidine Derivative K1586 Sensitizes Colorectal Cancer Cells to Ionizing Radiation by Inducing Chk1 Instability.

Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

Enhancing deep learning classification performance of tongue lesions in imbalanced data: mosaic-based soft labeling with curriculum learning.

BACKGROUND: Oral potentially malignant disorders (OPMDs) are associated with an increased risk of cancer of the oral cavity including the tongue. The early detection of oral cavity cancers and OPMDs is critical for reducing cancer-specific morbidity and mortality. Recently, there have been studies to apply the rapidly advancing technology of deep learning for diagnosing oral cavity cancer and OPMDs. However, several challenging issues such as class imbalance must be resolved to effectively train a deep learning model for medical imaging classification tasks. The aim of this study is to evaluate a new technique of artificial intelligence to improve the classification performance in an imbalanced tongue lesion dataset. METHODS: A total of 1,810 tongue images were used for the classification. The class-imbalanced dataset consisted of 372 instances of cancer, 141 instances of OPMDs, and 1,297 instances of noncancerous lesions. The EfficientNet model was used as the feature extraction model for classification. Mosaic data augmentation, soft labeling, and curriculum learning (CL) were employed to improve the classification performance of the convolutional neural network. RESULTS: Utilizing a mosaic-augmented dataset in conjunction with CL, the final model achieved an accuracy rate of 0.9444, surpassing conventional oversampling and weight balancing methods. The relative precision improvement rate for the minority class OPMD was 21.2%, while the relative [Formula: see text] score improvement rate of OPMD was 4.9%. CONCLUSIONS: The present study demonstrates that the integration of mosaic-based soft labeling and curriculum learning improves the classification performance of tongue lesions compared to previous methods, establishing a foundation for future research on effectively learning from imbalanced data.

GPA-Tree: statistical approach for functional-annotation-tree-guided prioritization of GWAS results.

MOTIVATION: In spite of great success of genome-wide association studies (GWAS), multiple challenges still remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), each with small or moderate effect sizes. Second, our understanding of the functional mechanisms through which genetic variants are associated with complex traits is still limited. To address these challenges, we propose GPA-Tree and it simultaneously implements association mapping and identifies key combinations of functional annotations related to risk-associated SNPs by combining a decision tree algorithm with a hierarchical modeling framework. RESULTS: First, we implemented simulation studies to evaluate the proposed GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs and identifying the true combinations of functional annotations with high accuracy. Second, we applied GPA-Tree to a systemic lupus erythematosus (SLE) GWAS and functional annotation data including GenoSkyline and GenoSkylinePlus. The results from GPA-Tree highlight the dysregulation of blood immune cells, including but not limited to primary B, memory helper T, regulatory T, neutrophils and CD8+ memory T cells in SLE. These results demonstrate that GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits. AVAILABILITY AND IMPLEMENTATION: The GPATree software is available at https://dongjunchung.github.io/GPATree/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Comparable humoral and cellular immunity against Omicron variant BA.4/5 of once-boosted BA.1/2 convalescents and twice-boosted COVID-19-naïve individuals.

The fourth vaccination dose confers additional protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with no prior coronavirus disease-19 (COVID-19). However, its immunological benefit against currently circulating BA.4/5 is unclear in individuals who have received a booster shot and been infected with Omicron variant BA.1/2. We analyzed immune responses in whom had been boosted once and did not have COVID-19 (n = 16), boosted once and had COVID-19 when BA.1/2 was dominant in Korea (Hybrid-6M group, n = 27), and boosted twice and did not have COVID-19 (Vx4 group, n = 15). Antibody binding activities against RBDo BA.1 and RBDo BA.4/5 , antigen-specific memory CD4+ and CD8+ T-cell responses against BA.4/5, and B-cell responses against SARS-CoV-2 wild-type did not differ statistically between the Hybrid-6M and Vx4 groups. The humoral and cellular immune responses of the Hybrid-6M group against BA.4/5 were comparable to those of the Vx4 group. Individuals who had been boosted and had an Omicron infection in early 2022 may not have high priority for an additional vaccination.

Tracking antigen-specific TCR clonotypes in SARS-CoV-2 infection reveals distinct severity trajectories.

Despite the importance of antigen-specific T cells in infectious disease, characterizing and tracking clonally amplified T cells during the progression of a patient's symptoms remain unclear. Here, we performed a longitudinal, in-depth single-cell multiomics analysis of samples from asymptomatic, mild, usual severe, and delayed severe patients of SARS-CoV-2 infection. Our in-depth analysis revealed that hyperactive or improper T-cell responses were more aggressive in delayed severe patients. Interestingly, tracking of antigen-specific T-cell receptor (TCR) clonotypes along the developmental trajectory indicated an attenuation in functional T cells upon severity. In addition, increased glycolysis and interleukin-6 signaling in the cytotoxic T cells were markedly distinct in delayed severe patients compared to usual severe patients, particularly in the middle and late stages of infection. Tracking B-cell receptor clonotypes also revealed distinct transitions and somatic hypermutations within B cells across different levels of disease severity. Our results suggest that single-cell TCR clonotype tracking can distinguish the severity of patients through immunological hallmarks, leading to a better understanding of the severity differences in and improving the management of infectious diseases by analyzing the dynamics of immune responses over time.

Bayesian causal inference for observational studies with missingness in covariates and outcomes.

Missing data are a pervasive issue in observational studies using electronic health records or patient registries. It presents unique challenges for statistical inference, especially causal inference. Inappropriately handling missing data in causal inference could potentially bias causal estimation. Besides missing data problems, observational health data structures typically have mixed-type variables - continuous and categorical covariates - whose joint distribution is often too complex to be modeled by simple parametric models. The existence of missing values in covariates and outcomes makes the causal inference even more challenging, while most standard causal inference approaches assume fully observed data or start their works after imputing missing values in a separate preprocessing stage. To address these problems, we introduce a Bayesian nonparametric causal model to estimate causal effects with missing data. The proposed approach can simultaneously impute missing values, account for multiple outcomes, and estimate causal effects under the potential outcomes framework. We provide three simulation studies to show the performance of our proposed method under complicated data settings whose features are similar to our case studies. For example, Simulation Study 3 assumes the case where missing values exist in both outcomes and covariates. Two case studies were conducted applying our method to evaluate the comparative effectiveness of treatments for chronic disease management in juvenile idiopathic arthritis and cystic fibrosis.

A Bayesian multivariate mixture model for high throughput spatial transcriptomics.

High throughput spatial transcriptomics (HST) is a rapidly emerging class of experimental technologies that allow for profiling gene expression in tissue samples at or near single-cell resolution while retaining the spatial location of each sequencing unit within the tissue sample. Through analyzing HST data, we seek to identify sub-populations of cells within a tissue sample that may inform biological phenomena. Existing computational methods either ignore the spatial heterogeneity in gene expression profiles, fail to account for important statistical features such as skewness, or are heuristic-based network clustering methods that lack the inferential benefits of statistical modeling. To address this gap, we develop SPRUCE: a Bayesian spatial multivariate finite mixture model based on multivariate skew-normal distributions, which is capable of identifying distinct cellular sub-populations in HST data. We further implement a novel combination of Pólya-Gamma data augmentation and spatial random effects to infer spatially correlated mixture component membership probabilities without relying on approximate inference techniques. Via a simulation study, we demonstrate the detrimental inferential effects of ignoring skewness or spatial correlation in HST data. Using publicly available human brain HST data, SPRUCE outperforms existing methods in recovering expertly annotated brain layers. Finally, our application of SPRUCE to human breast cancer HST data indicates that SPRUCE can distinguish distinct cell populations within the tumor microenvironment. An R package spruce for fitting the proposed models is available through The Comprehensive R Archive Network.

In Vivo Serotonin 5-HT2A Receptor Availability and Its Relationship with Aggression Traits in Healthy Individuals: A Positron Emission Tomography Study with C-11 MDL100907.

Serotonergic neurotransmission has been associated with aggression in several psychiatric disorders. Human aggression is a continuum of traits, ranging from normal to pathological phenomena. However, the individual differences in serotonergic neurotransmission and their relationships with aggression traits in healthy individuals remain unclear. In this study, we explored the relationship between 5-HT2A receptor availability in vivo and aggression traits in healthy participants. Thirty-three healthy participants underwent 3-Tesla magnetic resonance imaging and positron emission tomography (PET) with [11C]MDL100907, a selective radioligand for 5-HT2A receptors. To quantify 5-HT2A receptor availability, the binding potential (BPND) was derived using the basis function implementation of the simplified reference tissue model, with the cerebellum as the reference region. The participants' aggression levels were assessed using the Buss-Perry Aggression Questionnaire. The voxel-based correlation analysis with age and sex as covariates revealed that the total aggression score was significantly positively correlated with [11C]MDL100907 BPND in the right middle temporal gyrus (MTG) pole, left fusiform gyrus (FUSI), right parahippocampal gyrus, and right hippocampus. The physical aggression subscale score had significant positive correlations with [11C]MDL100907 BPND in the left olfactory cortex, left orbital superior frontal gyrus (SFG), right anterior cingulate and paracingulate gyri, left orbitomedial SFG, left gyrus rectus, left MTG, left inferior temporal gyrus, and left angular gyrus. The verbal aggression subscale score showed significant positive correlations with [11C]MDL100907 BPND in the bilateral SFG, right medial SFG, left FUSI, and right MTG pole. Overall, our findings suggest the possibility of positive correlations between aggression traits and in vivo 5-HT2A receptor availability in healthy individuals. Future research should incorporate multimodal neuroimaging to investigate the downstream effects of 5-HT2A receptor-mediated signaling and integrate molecular and systems-level information in relation to aggression traits.

Broad humoral and cellular immunity elicited by one-dose mRNA vaccination 18 months after SARS-CoV-2 infection.

BACKGROUND: Practical guidance is needed regarding the vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals in resource-limited countries. It includes the number of vaccine doses that should be given to unvaccinated patients who experienced COVID-19 early in the pandemic. METHODS: We recruited COVID-19 convalescent individuals who received one or two doses of an mRNA vaccine within 6 or around 18 months after a diagnosis of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Their samples were assessed for IgG-binding or neutralizing activity and cell-mediated immune responses against SARS-CoV-2 wild-type and variants of concern. RESULTS: A total of 43 COVID-19 convalescent individuals were analyzed in the present study. The results showed that humoral and cellular immune responses against SARS-CoV-2 wild-type and variants of concern, including the Omicron variant, were comparable among patients vaccinated within 6 versus around 18 months. A second dose of vaccine did not significantly increase immune responses. CONCLUSION: One dose of mRNA vaccine should be considered sufficient to elicit a broad immune response even around 18 months after a COVID-19 diagnosis.

The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells.

Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.

IL-7Rαlow CD8+ T Cells from Healthy Individuals Are Anergic with Defective Glycolysis.

Effector memory (EM) CD8+ T cells expressing lower levels of IL-7R α (IL-7Rαlow) from healthy individuals are partly compromised in vitro, but the identity of these cells has remained unclear. In this study, we demonstrate that human IL-7Rαlow EM CD8+ T cells are naturally occurring anergic cells in vivo and impaired in proliferation and IL-2 production but competent in IFN-γ and TNF-α production, a state that can be restored by IL-2 stimulation. IL-7Rαlow EM CD8+ T cells show decreased expression of GATA3 and c-MYC and are defective in metabolic reprogramming toward glycolysis, a process required for the proliferation of T cells. However, IL-7Rαlow EM CD8+ T cells can proliferate with TCR stimulation in the presence of IL-2 and IL-15, suggesting that these cells can be restored to normality or increased activity by inflammatory conditions and may serve as a reservoir for functional immunity.

Effects of remote ischemic preconditioning on platelet activation and reactivity in patients undergoing cardiac surgery using cardiopulmonary bypass: a randomized controlled trial.

During cardiopulmonary bypass (CPB), platelet activation and dysfunction are associated with adverse outcomes. Remote ischemic preconditioning (RIPC) has been shown to attenuate platelet activation. We evaluated the effects of RIPC on platelet activation during CPB in patients undergoing cardiac surgery. Among 58 randomized patients, 26 in the RIPC group and 28 in the sham-RIPC group were analyzed. RIPC consisted of 4 cycles of 5-min ischemia induced by inflation of pneumatic cuff pressure to 200 mmHg, followed by 5-min reperfusion comprising deflation of the cuff on the upper arm. Platelet activation was assessed using flow cytometry analysis of platelet activation markers. The primary endpoint was the AUC of CD62P expression during the first 3 h after initiation of CPB. Secondary outcomes were the AUC of PAC-1 expression and monocyte-platelet aggregates (MPA) during 3 h of CPB. The AUCs of CD62P expression during 3 h after initiation of CPB were 219.4 ± 43.9 and 211.0 ± 41.2 MFI in the RIPC and sham-RIPC groups, respectively (mean difference, 8.42; 95% CI, -14.8 and 31.7 MFI; p =.471). The AUCs of PAC-1 expression and MPA did not differ between groups. RIPC did not alter platelet activation and reactivity during CPB in patients undergoing cardiac surgery.

Longitudinal Analysis of Human Memory T-Cell Response According to the Severity of Illness up to 8 Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: Understanding the memory T-cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for assessing the longevity of protective immunity after SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. However, the longitudinal memory T-cell response up to 8 months post-symptom onset (PSO) according to the severity of illness is unknown. METHODS: We analyzed peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with COVID-19 who experienced asymptomatic, mild, or severe illness at 2, 5, and 8 months PSO. SARS-CoV-2 spike, nucleocapsid, and membrane protein-stimulated PBMCs were subjected to flow cytometry analysis. RESULTS: A total of 24 patients (7 asymptomatic, 9 with mild disease, and 8 with severe disease) and 6 healthy volunteers were analyzed. SARS-CoV-2-specific OX40+CD137+CD4+ T cells and CD69+CD137+CD8+ T cells persisted at 8 months PSO. Also, antigen-specific cytokine-producing or polyfunctional CD4+ T cells were maintained for up to 8 months PSO. Memory CD4+ T-cell responses tended to be greater in patients who had severe illness than in those with mild or asymptomatic disease. CONCLUSIONS: Memory response to SARS-CoV-2, based on the frequency and functionality, persists for 8 months PSO. Further investigations involving its longevity and protective effect from reinfection are warranted.

Polymorphism in the MAGI2 Gene Modifies the Effect of Amyloid ß on Neurodegeneration.

INTRODUCTION: A weak association between amyloid ß (Aß) deposition and neurodegeneration biomarkers, such as brain atrophy, has been repeatedly reported in a subset of patients with Alzheimer disease, suggesting individual differences in response to Aß deposition. METHODS: Here, we performed a genome-wide interaction study to identify single-nucleotide polymorphism (SNP) that modify the effect of Aß (measured by 18F-florbetapir positron emission tomography) on brain atrophy (measured by cortical thickness using magnetic resonance imaging). We used magnetic resonance imaging, positron emission tomography, cerebrospinal fluid, and genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database [discovery cohort, ADNI-GO/2 (n=723) and replication cohort, ADNI-1 (n=129)]. RESULTS: We identified a genome-wide suggestive interaction of rs3807779 SNP (ß=-0.14, SE=0.029, P=9.08×10-7) in the discovery cohort. The greater dosage of rs3807779 SNP increased the detrimental effect of Aß deposition on cortical thickness. In replication analyses, the congruent results were replicated to confirm our findings. Furthermore, rs3807779 SNP augmented the detrimental effect of Aß deposition on cognitive function. Genetic profiling showed that rs3807779 has chromatin interactions with the promoter region of MAGI2 gene, suggesting its association with MAGI2 expression. CONCLUSIONS: These findings demonstrate that subjects carrying the rs3807779 SNP are more susceptible to Aß-related neurodegeneration.

Cell-Mediated Immunogenicity of Influenza Vaccination in Patients With Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND: We assessed cell-mediated immune (CMI) responses of influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs), which remain elusive. METHODS: Vaccine-elicited CMI responses in patients receiving ICIs or cytotoxic agents were investigated by flow cytometry. Polyfunctional cells were defined as T cells that express 2 or more of interleukin 2 (IL-2), interleukin 4 (IL-4), interferon gamma (IFN-γ), and CD107a. An adequate CMI response was defined as an increase of polyfunctional T cells against both H1N1 and H3N2 strains. RESULTS: When comparing ICI (n = 11) and cytotoxic chemotherapy (n = 29) groups, H1N1-specific IL-4 or IFN-γ-expressing CD4+ T cells, IL-2, IL-4, IFN-γ, or CD107a-expressing CD8+ T cells, H3N2-specific IFN-γ-expressing CD4+ T cells, and CD107a-expressing CD8+ T cells were more frequent in the ICI group. Fold changes in polyfunctional H3N2-specific CD4+ (median, 156.0 vs 95.7; P = .005) and CD8+ (155.0 vs 103.4; P = .044) T cells were greater in the ICI group. ICI administration was strongly associated with an adequate CMI response for both CD4+ and CD8+ T cells (P = .003). CONCLUSIONS: CMI responses following influenza vaccination were stronger in the ICI group than in the cytotoxic chemotherapy group. Influenza vaccination should be strongly recommended in patients with cancer receiving ICIs.

Kidney residency of VISTA-positive macrophages accelerates repair from ischemic injury.

Tissue-resident macrophages have unique tissue-specific functions in maintaining homeostasis and resolving inflammation. However, the repair role and relevant molecules of kidney-resident macrophages after ischemic injury remain unresolved. To this end, mice without kidney-resident R1 macrophages but containing infiltrating monocyte-derived R2 macrophages were generated using differential cellular kinetics following clodronate liposome treatment. When ischemia-reperfusion injury was induced in these mice, late phase repair was reduced. Transcriptomic and flow cytometric analyses identified that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint molecule, was constitutively expressed in kidney-resident R1 macrophages, but not in other tissue-resident macrophages. Here, VISTA functioned as a scavenger of apoptotic cells and served as a checkpoint to control kidney-infiltrating T cells upon T cell receptor-mediated stimulation. Together these functions improved the repair process after ischemia-reperfusion injury. CD14+ CD33+ mononuclear phagocytes of human kidney also expressed VISTA, which has similar functions to the mouse counterpart. Thus, VISTA is upregulated in kidney macrophages in a tissue-dependent manner and plays a repair role during ischemic injury.

Identifying the Functional Brain Network of Motor Reserve in Early Parkinson's Disease.

BACKGROUND: The severity of motor symptoms in Parkinson's disease (PD) does not always correlate with the degree of nigral dopaminergic neuronal loss. Individuals with greater motor reserve may have milder motor signs than their striatal dopamine loss. In this study, we explored the functional brain network associated with motor reserve in early-stage PD. METHODS: We analyzed 134 patients with de novo PD who underwent dopamine transporter scans and resting-state functional magnetic resonance imaging. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We applied network-based statistic analysis to identify the functional brain network associated with the measure of motor reserve (ie, motor reserve network). We also assessed the effect of motor reserve network connectivity strength on the longitudinal increase in levodopa-equivalent dose during the 2-year follow-up period. RESULTS: Network-based statistic analysis identified the motor reserve network composed of the basal ganglia, inferior frontal cortex, insula, and cerebellar vermis at a primary threshold of P value 0.001. Patients with an increased degree of functional connectivity within the motor reserve network had greater motor reserve. There was a significant interaction between the motor reserve network strength and time in the linear mixed model, indicating that higher motor reserve network strength was associated with slower longitudinal increase in levodopa-equivalent dose. CONCLUSIONS: The present study revealed the functional brain network associated with motor reserve in patients with early-stage PD. Functional connections within the motor reserve network are associated with the individual's capacity to cope with PD-related pathologies. © 2020 International Parkinson and Movement Disorder Society.

Alexithymia and frontal-amygdala functional connectivity in North Korean refugees.

BACKGROUND: Refugees commonly experience difficulties with emotional processing, such as alexithymia, due to stressful or traumatic experiences. However, the functional connectivity of the amygdala, which is central to emotional processing, has yet to be assessed in refugees. Thus, the present study investigated the resting-state functional connectivity of the amygdala and its association with emotional processing in North Korean (NK) refugees. METHODS: This study included 45 NK refugees and 40 native South Koreans (SK). All participants were administered the Toronto Alexithymia Scale (TAS), Beck Depression Inventory (BDI), and Clinician-administered PTSD Scale (CAPS), and differences between NK refugees and native SK in terms of resting-state functional connectivity of the amygdala were assessed. Additionally, the association between the strength of amygdala connectivity and the TAS score was examined. RESULTS: Resting-state connectivity values from the left amygdala to the bilateral dorsolateral prefrontal cortex (dlPFC) and dorsal anterior cingulate cortex (dACC) were higher in NK refugees than in native SK. Additionally, the strength of connectivity between the left amygdala and right dlPFC was positively associated with TAS score after controlling for the number of traumatic experiences and BDI and CAPS scores. CONCLUSIONS: The present study found that NK refugees exhibited heightened frontal-amygdala connectivity, and that this connectivity was correlated with alexithymia. The present results suggest that increased frontal-amygdala connectivity in refugees may represent frontal down-regulation of the amygdala, which in turn may produce alexithymia.

Detection of gray matter microstructural changes in Alzheimer's disease continuum using fiber orientation.

BACKGROUND: This study aimed to investigate feasible gray matter microstructural biomarkers with high sensitivity for early Alzheimer's disease (AD) detection. We propose a diffusion tensor imaging (DTI) measure, "radiality", as an early AD biomarker. It is the dot product of the normal vector of the cortical surface and primary diffusion direction, which reflects the fiber orientation within the cortical column. METHODS: We analyzed neuroimages from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including images from 78 cognitively normal (CN), 50 early mild cognitive impairment (EMCI), 34 late mild cognitive impairment (LMCI), and 39 AD patients. We then evaluated the cortical thickness (CTh), mean diffusivity (MD), which are conventional AD magnetic resonance imaging (MRI) biomarkers, and the amount of accumulated amyloid and tau using positron emission tomography (PET). Radiality was projected on the gray matter surface to compare and validate the changes with different stages alongside other neuroimage biomarkers. RESULTS: The results revealed decreased radiality primarily in the entorhinal, insula, frontal, and temporal cortex with further progression of disease. In particular, radiality could delineate the difference between the CN and EMCI groups, while the other biomarkers could not. We examined the relationship between radiality and other biomarkers to validate its pathological evidence in AD. Overall, radiality showed a high association with conventional biomarkers. Additional ROI analysis revealed the dynamics of AD-related changes as stages onward. CONCLUSION: Radiality in cortical gray matter showed AD-specific changes and relevance with other conventional AD biomarkers with high sensitivity. Moreover, radiality could identify the group differences seen in EMCI, representative of changes in early AD, which supports its superiority in early diagnosis compared to that possible with conventional biomarkers. We provide evidence of structural changes with cognitive impairment and suggest radiality as a sensitive biomarker for identifying early AD.