Search

In eukaryotes, higher-order chromatin organization is spatiotemporally regulated as domains, for various cellular functions. However, their physical nature in living cells remains unclear (e.g., condensed domains or extended fiber loops; liquid-like or solid-like). Using novel approaches combining genomics, single-nucleosome imaging, and computational modeling, we investigated the physical organization and behavior of early DNA replicated regions in human cells, which correspond to Hi-C contact domains with active chromatin marks. Motion correlation analysis of two neighbor nucleosomes shows that nucleosomes form physically condensed domains with ~150-nm diameters, even in active chromatin regions. The mean-square displacement analysis between two neighbor nucleosomes demonstrates that nucleosomes behave like a liquid in the condensed domain on the ~150 nm/~0.5 s spatiotemporal scale, which facilitates chromatin accessibility. Beyond the micrometers/minutes scale, chromatin seems solid-like, which may contribute to maintaining genome integrity. Our study reveals the viscoelastic principle of the chromatin polymer; chromatin is locally dynamic and reactive but globally stable.

Although altered networks inside the hippocampus (hippocampal intra-networks) have been observed in dementia, the evaluation of hippocampal intra-networks using magnetic resonance imaging (MRI) is challenging. We employed conventional structural imaging and incident component analysis (ICA) to investigate the structural covariance of the hippocampal intra-networks. We aimed to assess altered hippocampal intra-networks in patients with mild cognitive impairment (MCI). A cross-sectional study of 2122 participants with 3T MRI (median age 69 years, 60.9% female) were divided into 218 patients with MCI and 1904 cognitively normal older adults (CNOA). By employing 3D T1-weighted imaging and ICA, we extracted the structural covariance intra-networks in the hippocampus. The ICA extracted 16 intra-networks from the hippocampal structural images, which were divided into two bilateral networks and 14 ipsilateral networks. Of the 16 intra-networks, four (one bilateral network and three ipsilateral networks) were significant predictors of MCI from the CNOA after adjusting for age, sex, education, disease history, and hippocampal volume/total intracranial volume ratio. In conclusion, we found that the relationship between hippocampal intra-networks and MCI was independent from the hippocampal volume. Our results suggest that altered hippocampal intra-networks may reflect a different pathology in MCI from that of brain atrophy.

ObjectiveThis study aimed to seek a new method of evaluation and surrogate markers for diffuse neuropsychiatric SLE (NPSLE).MethodsWe enrolled 44 patients with SLE between 2017 and 2020 who fulfilled at least one of three specific inclusion criteria: high disease activity, abnormal findings (cerebrospinal fluid [CSF] examination, brain MRI, or electroencephalography), or history of neuropsychiatric illness. Psychiatric symptom rating scales (PSYRATS) were evaluated retrospectively. The primary end point was the PSYRATS positivity rate in SLE patients who had not been diagnosed with diffuse NPSLE.ResultsBased on the 1999 ACR classifications, 7 out of the 44 patients evaluated using PSYRATS had been diagnosed with diffuse NPSLE. PSYRATS positivity was seen in 13 out of 37 SLE patients (35.1%) who had not been diagnosed with diffuse NPSLE, and all these patients were positive for Montgomery–Åsberg Depression Rating Scale (MADRS), an indicator of depression state in PSYRATS. Additionally, in the 20 SLE patients exhibiting depression symptoms who were MADRS-positive, CSF concentrations of the neuroinflammatory markers homovanillic acid (HVA; P = 0.0400), stromal cell-derived factor-1α (SDF-1α; P = 0.0431) and stem cell growth factor-β (SCGF-1β; P = 0.0061) were significantly reduced compared with the 24 MADRS-negative SLE patients, and the levels of HVA, SDF-1α and SCGF-1β correlated with one another (P ConclusionMany patients with active SLE have subclinical depression, and MADRS evaluation of neuropsychiatric symptoms is useful for detecting them. Additionally, the decrease in CSF levels of HVA, SDF-1 α and SCGF-1β reflects the same pathology, and these may serve as surrogate markers.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, ｗe conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HCs). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 AMBP) and 92 HCs using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: University Hospital Medical Information Network Individual Case Data Repository: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303

A 60-year-old woman with a 37-year history of rheumatoid arthritis (RA) had a sudden onset of headache. Head MRI showed acute multiple infarctions in the vertebrobasilar region, and MR angiography showed stenosis of the right vertebral artery (VA). 3D-CT angiography of the craniovertebral junction showed atlantoaxial subluxation and stenosis of the right VA just distal to the transverse foramen of C2, which was due to osteophytes and degenerative changes secondary to RA. Digital subtraction angiography clearly demonstrated occlusion of the right VA during rightward head rotation. Based on those findings, rotatory instability at C1-2 was considered as the primary cause of the vertebrobasilar infarctions, and Bow Hunter's syndrome was diagnosed. The patient underwent C1-5 posterior fixation, and brain infarction has not recurred.

Eukaryotic genome DNA is wrapped around core histones and forms a nucleosome structure. Together with associated proteins and RNAs, these nucleosomes are organized three-dimensionally in the cell as chromatin. Emerging evidence demonstrates that chromatin consists of rather irregular and variable nucleosome arrangements without the regular fiber structure and that its dynamic behavior plays a critical role in regulating various genome functions. Single-nucleosome imaging is a promising method to investigate chromatin behavior in living cells. It reveals local chromatin motion, which reflects chromatin organization not observed in chemically fixed cells. The motion data is like a gold mine. Data analyses from many aspects bring us more and more information that contributes to better understanding of genome functions. In this review article, we describe imaging of single-nucleosomes and their tracked behavior through oblique illumination microscopy. We also discuss applications of this technique, especially in elucidating nucleolar organization in living cells.

The human primary auditory cortex is located in the Heschl's gyrus (HG). To assess the intrinsic MR property in the gray matter of the HG (GM-HG) with T1 and T2 values using a commercially available MR fingerprinting (MRF) technique.The subjects were 10 healthy volunteers (with 20 HGs; mean age, 31.5 years old; range, 25-53 years old). Coronal T1 and T2 maps were obtained with commercially available MRF using a 3-Tesla MR system. Two radiologists measured the T1 and T2 values of the GM-HG, the GM in the superior temporal gyrus (GM-STG), and the GM in the middle temporal gyrus (GM-MTG) by drawing a ROI on coronal maps.For both radiologists, the mean T1 and T2 values of the GM-HG were significantly lower than those in the GM-STG or GM-MTG (P0.01). The interobserver reliability using the intraclass correlation coefficients (ICC) (2,1) showed strong agreement for the measurement of the T1 and T2 values (ICCs =⃥ 0.80 and 0.78 for T1 and T2 values, respectively).The T1 and T2 values on MRF for the GM-HG were lower than those for the GM-STG and GM-MTG, likely reflecting a higher myelin content and iron deposition in the GM-HG. Quantitative measurements using the MRF can clarify cortical properties with high reliability, which may indicate that MRF mapping provides new insights into the structure of the human cortical GM.

Background Synthetic magnetic resonance imaging (SyMRI) enables to reformat various images by adjusting the MR parameters. Purpose To investigate whether customization of the repetition time (TR), echo time (TE), and inversion time (TI) in SyMRI could improve the visualization of subthalamic nucleus (STN). Material and Methods We examined five healthy volunteers using both coronal SyMRI and quantitative susceptibility mapping (QSM), seven patients with Parkinson's disease (PD) using coronal SyMRI, and 15 patients with PD using coronal QSM. Two neuroradiologists reformatted SyMRI (optimized SyMRI) by adjusting TR, TE, and TI to achieve maximum tissue contrast between the STN and the adjacent brain parenchyma. The optimized MR parameters in the PD patients varied according to the individual. For regular SyMRI (T2-weighted imaging [T2WI] and STIR), optimized SyMRI, and QSM, qualitative visualization scores of the STN (STN score) were recorded. The contrast-to-noise ratio (CNR) of the STN was also measured. Results For the STN scores in both groups, the optimized SyMRI were significantly higher than the regular SyMRI ( P Conclusions On SyMRI, optimization of MR parameters (TR, TE, and TI) on an individual basis may be useful to increase the conspicuity of the STN.

Background: Depressive state is a common complication of spinocerebellar ataxia type 3 (SCA3). To the best of our knowledge, cases of SCA3 presenting with psychotic symptoms (i.e., cenesthopathy) have not been described. Here, we present a case of severe depressive state with cenesthopathy and delusion in a young Japanese man with SCA3.Case presentation: A 43-year-old Japanese man with SCA3 developed severe depressive state with associated cenesthopathy and delusion. He was treated with escitalopram (10 mg/day) and olanzapine (2.5 mg/day). Computed tomography showed atrophy of the cerebellum, bilateral superior cerebellar peduncle, and tegmentum of the pons. Single-photon emission computed tomography demonstrated reduced blood flow in the cerebellum, vermis, and brainstem. After eight weeks, his depressive state and delusion improved however his cenesthopathy persisted. Conclusions: We encountered a case of severe state with psychotic features (i.e., cenesthopathy and delusion) in a young Japanese man with SCA3. This study demonstrates that SCA3 may inherently present with severe depressive state and unique psychotic symptoms, even in younger patients where age-related neurodegeneration is unlikely. The complex function of the cerebellum in emotion and perception may play a crucial in the emergence of these psychiatric symptoms.

Background Knowing chromatin components at a DNA regulatory element at any given time is essential for understanding how the element works during cellular proliferation, differentiation and development. A region-specific chromatin purification is an invaluable approach to dissecting the comprehensive chromatin composition at a particular region. Several methods (e.g., PICh, enChIP, CAPTURE and CLASP) have been developed for isolating and analyzing chromatin components. However, all of them have some shortcomings in identifying non-coding RNA associated with DNA regulatory elements. Results We have developed a new approach for affinity purification of specific chromatin segments employing an N-methyl pyrrole (P)-N-methylimidazole (I) (PI) polyamide probe, which binds to a specific sequence in double-stranded DNA via Watson–Crick base pairing as a minor groove binder. This new technique is called proteomics and RNA-omics of isolated chromatin segments (PI-PRICh). Using PI-PRICh to isolate mouse and human telomeric components, we found enrichments of shelterin proteins, the well-known telomerase RNA component (TERC) and telomeric repeat-containing RNA (TERRA). When PI-PRICh was performed for alternative lengthening of telomere (ALT) cells with highly recombinogenic telomeres, in addition to the conventional telomeric chromatin, we obtained chromatin regions containing telomeric repeat insertions scattered in the genome and their associated RNAs. Conclusion PI-PRICh reproducibly identified both the protein and RNA components of telomeric chromatin when targeting telomere repeats. PI polyamide is a promising alternative to simultaneously isolate associated proteins and RNAs of sequence-specific chromatin regions under native conditions, allowing better understanding of chromatin organization and functions within the cell.

BACKGROUND In amyotrophic lateral sclerosis (ALS), motor neurons in the brainstem markedly deplete, whereas sensory neurons are less severely affected. PURPOSE To determine whether facial nerve (FN) measurement on 3D fast imaging employing steady-state acquisition (FIESTA) is useful for ALS diagnosis. STUDY TYPE Retrospective. SUBJECTS Fifteen ALS patients and 16 controls. FIELD STRENGTH/SEQUENCE 3T FIESTA MR. ASSESSMENT The cross-sectional area of the FN and cochlear nerve (CN) were measured, and the FN/CN ratio (FCR) was assessed. For qualitative assessment, the FN cross-sectional area was compared with that of the CN and the following scores were assigned: score 1 (large), the FN is larger than the CN; score 2 (almost equal), the size difference between the FN and CN is within 10%; score 3 (small), the FN is smaller than the CN (10-50%); score 4 (significantly small), size of the FN is less than half the size of the CN. STATISTICAL TESTS The differences in FCR between the ALS patients and the controls were tested using the Wilcoxon Mann-Whitney U-test. For the qualitative and quantitative assessments, we performed a receiver operating characteristic analysis for the diagnosis of ALS with an abnormal finding as score 3 or 4. RESULTS The mean FCR was significantly smaller for ALS patients (0.71 ± 0.17) than for controls (0.95 ± 0.08) (P < 0.001) and the area under the curve was 0.93. When an FN score was 3 or 4, indicative of FN atrophy, the sensitivity and specificity values of FIESTA for discriminating ALS patients from controls were 93.3% (14/15) and 90.0% (18/20), respectively. DATA CONCLUSION The FN atrophy revealed on FIESTA, which may reflect lower motor neuron impairment in ALS, allowed us to distinguish ALS patients from controls with a high degree of accuracy. LEVEL OF EVIDENCE 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:757-766.

Chromatin in eukaryotic cells is a negatively charged polymer composed of DNA, histones, and various associated proteins. Over the past ten years, our view of chromatin has shifted from a static regular structure to a dynamic and highly variable configuration. While the details are not fully understood yet, chromatin forms numerous compact domains that act as dynamic functional units of the genome in higher eukaryotes. By altering DNA accessibility, the dynamic nature of chromatin governs various genome functions including RNA transcription, DNA replication, and DNA repair/recombination. Based on the new evidence coming from both genomics and imaging studies, we discuss the structural and dynamic aspects of chromatin and their biological relevance in the living cell.

Background Metastatic brain tumors and glioblastomas are the 2 of the most common brain neoplasms in adults. However, distinguishing solitary metastatic brain tumors from glioblastomas on conventional magnetic resonance imaging remains particularly challenging. Thus, we aimed to retrospectively assess the role of contrast-enhanced fast imaging employing steady-state acquisition (CE-FIESTA) imaging in distinguishing between metastatic brain tumors and glioblastomas. Materials and Methods Forty-three patients with metastatic brain tumors and 14 patients with glioblastomas underwent conventional magnetic resonance imaging and CE-FIESTA before surgery. First, 1 neuroradiologist and 1 neurosurgeon classified the CE-FIESTA findings for the peritumoral brain parenchyma by consensus. Next, the 2 neuroradiologists performed an observer performance study comparing tumor shape classification (smooth or irregular margins), a classic imaging finding, with the CE-FIESTA classification of the peritumoral brain parenchyma. Results The CE-FIESTA findings for the peritumoral brain parenchyma were classified as follows: type A, no hyperintense rim; type B, partial hyperintense rim; and type C, extended hyperintense rim. With regard to the diagnosis of metastatic brain tumors, the observer performance study demonstrated that the mean sensitivity, specificity, and accuracy of an extended hyperintense rim classification (type C) on CE-FIESTA images were 95.3%, 85.7%, and 93.0%, respectively. The accuracy of the CE-FIESTA classification was significantly higher than that of the tumor shape classification. Conclusions CE-FIESTA images may provide useful information for distinguishing metastatic brain tumors from glioblastomas, especially when focusing on differences in the peritumoral brain parenchyma.

Alcohol, 1,6-hexanediol, is widely used for melting liquid droplets formed by liquid0–liquid phase separation; however, it can also seriously affect cells by immobilizing and condensing chromatin., Liquid droplets formed inside the cell by liquid–liquid phase separation maintain membrane-less condensates/bodies (or compartments). These droplets are important for concentrating certain molecules and facilitating spatiotemporal regulation of cellular functions. 1,6-hexanediol (1,6-HD), an aliphatic alcohol, inhibits weak hydrophobic protein–protein/protein-RNA interactions required for the droplet formation (droplet melting activity) and is used here to elucidate the formation process of cytoplasmic/nuclear condensates/bodies. However, the effect of 1,6-HD on chromatin in living cells remains unclear. We found that 1,6-HD drastically suppresses chromatin motion and hyper-condenses chromatin in human cells by using live-cell single-nucleosome imaging, which detects changes in the state of chromatin. These effects were enhanced in a dose-dependent manner. Chromatin was “frozen” by 5%, or higher, concentrations of 1,6-HD. 1,6-HD greatly facilitated cation-dependent chromatin condensation in vitro. This 1,6-HD action is distinct from its melting activity of liquid droplets. Alcohols, such as 1,6-HD, appear to remove water molecules around chromatin and locally condense chromatin. Therefore, liquid droplet results obtained using 1,6-HD should be carefully interpreted or reconsidered when these droplets are associated with chromatin.

Single-molecule imaging and tracking reveal how rRNA transcription is regulated by phase separation in the nucleolus., The nucleolus is a nuclear body with multiphase liquid droplets for ribosomal RNA (rRNA) transcription. How rRNA transcription is regulated in the droplets remains unclear. Here, using single-molecule tracking of RNA polymerase I (Pol I) and chromatin-bound upstream binding factor (UBF), we reveal suppression of transcription with phase separation. For transcription, active Pol I formed small clusters/condensates that constrained rDNA chromatin in the nucleolus fibrillar center (FC). Treatment with a transcription inhibitor induced Pol I to dissociate from rDNA chromatin and to move like a liquid within the nucleolar cap that transformed from the FC. Expression of a Pol I mutant associated with a craniofacial disorder inhibited transcription by competing with wild-type Pol I clusters and transforming the FC into the nucleolar cap. The cap droplet excluded an initiation factor, ensuring robust silencing. Our findings suggest a mechanism of rRNA transcription suppression via phase separation of intranucleolar molecules governed by Pol I.

We evaluated cerebral gyri (CG) on phase difference enhanced imaging (PADRE) of corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Parkinson's disease (PD) patients to determine whether it is possible to discriminate among them on an individual basis. Two radiologists reviewed appearance of the normal CG and that of CBS patients on PADRE, and deviations from the appearance of the normal CG were recorded. Next, based on the CG abnormalities, two other reviewers reviewed PADRE images from 12 CBS, 14 PSP, and 30 PD patients. In healthy subjects on the PADRE images, the signal intensity (SI) of the gray matter (GM) was homogeneously, slightly hyperintense to the subcortical white matter (SCWM), and the SI of the SCWM was homogeneously hypointense. In CBS patients, hypointense layer in superficial GM and disappearance of hypointense in SCWM. The frequency of the abnormal findings on PADRE in the blinded manner by two readers was 100% (12/12), 3% (1/30), and 29% (4/14 in Reader 1) or 36% (5/14 in Reader 2) in CBS PD, and PSP patients, respectively. Laterality of the PADRE findings was showed in 12 (100%) CBS patients and 3 (21%) PSP, but not in any PD patients. The previously reported typical findings in CBS on conventional magnetic resonance image (MRIs) were observed in only 42% (5/12) of CBS patients. In conclusion, the abnormal findings in CG on PADRE appears more useful than conventional MRI findings for discriminating CBS from PD on an individual basis.

This study aims to investigate hippocampal subfield volumes in patients with hippocampal sclerosis (HS) without visually detectable MRI abnormalities and to determine the diagnostic accuracy using hippocampal subfield volumes. We examined 46 patients with unilateral HS who had a histopathological diagnosis, and 54 controls. The patients were divided into two groups; visually detectable HS (n = 26) and undetectable HS (n = 20) on MRI. The volumes of hippocampal subfield using FreeSurfer were compared among the three groups. Diagnostic accuracy was calculated as the AUC of ROC using cutoff values for each individual subfield. Compared with the controls, visually detectable HS showed significantly reduced volumes of all the hippocampal subfields and entire hippocampus, whereas visually undetectable HS showed significant atrophy only in the CA3 and hippocampus-amygdala-transition-area. To diagnose visually undetectable HS, the CA3 volumes had AUC of 0.719, which was higher than AUC of 0.614 based on the entire hippocampal volumes. Visually undetectable HS demonstrated volume reductions in the CA3. Further, the CA3 volumes was more useful to diagnose visually undetectable HS compared with the entire hippocampal volumes.

BACKGROUND Systemic lupus erythematosus (SLE) is related to vasculitis, which causes brain infarctions; however, the pathology of large cerebral vessels has not been fully established. PURPOSE To demonstrate the prevalence of vessel wall lesions (VWLs) in SLE patients using 3D vessel wall imaging and to assess the relationship between VWLs and brain infarctions. STUDY TYPE Retrospective. SUBJECTS Sixty SLE patients and 50 healthy subjects (HS). FIELD STRENGTH/SEQUENCE Each subject underwent 3T MRI, which included 3D FSE PDWI (CUBE). ASSESSMENT For each of the 33 segments of the intracranial artery (internal carotid artery ∼ M3 segment of middle cerebral artery [MCA]), the VWLs were scored as either positive or negative, and the VWL score was calculated as the sum of the segments with VWLs. We also evaluated brain lesions on conventional MRI. STATISTICAL TESTS We used logistic regression analyses to determine the clinical (serological test and cardiovascular risk factors) and imaging characteristics associated with infarctions in SLE patients. RESULTS For the peripheral vessels such as MCA, VWLs were more common for SLE patients than for HS (43.3% versus 16.7% in M1 segment, 60.4% versus 16.7% in M2 segment, both P

Individuals with s/s genotype of serotonin transporter gene-linked promotor region (5-HTTLPR), which appear with a high frequency in Japanese, exhibit more diagnosable depression in relation to stressful life events than those with the s/l or l/l genotype. We prospectively investigated the brain volume changes in first-episode and medication naïve major depression disorder patients (MDD) with the s/s genotype in Japanese. We assessed the differences between 27 MDD with the s/s genotype and 44 healthy subjects (HS) with the same genotype using a whole-brain voxel-by-voxel statistical analysis of MRI. Gray matter volume in a brain region with significant clusters obtained via voxel-based morphometry analysis were measured and, as an exploratory analysis, evaluated for relationships to the subcategory scores (core, sleep, activity, psychic, somatic anxiety, delusion) of the Hamilton Depression Rating Scale (HAM-D) and the Social Readjustment Rating Scale (SRRS). The brain volume in the left insula lobe was significantly smaller in the MDD than in the HS. The left insula lobe volume correlated negatively with the “psychic” score of HAM-D and the SRRS. In a Japanese population with the s/s genotype, we found an atrophy of the insula in the MDD, which might be associated with “psychic” symptom and stress events.

To assess the utility of the motion correction method with prospective motion correction (PROMO) in a voxel-based morphometry (VBM) analysis for ‘uncooperative’ patient populations. High-resolution 3D T1-weighted imaging both with and without PROMO were performed in 33 uncooperative patients with Parkinson's disease (n = 11) or dementia (n = 22). We compared the grey matter (GM) volumes and cortical thickness between the scans with and without PROMO. For the mean total GM volume with the VBM analysis, the scan without PROMO showed a significantly smaller volume than that with PROMO (p

Using orientation-independent-DIC microscopy, we revealed that the density of total materials in heterochromatin was only 1.53-fold higher than that of euchromatin, whereas the DNA density was 7.5-fold higher. This surprisingly small difference may be due to the dominance of proteins and RNAs in both chromatins, which may help create a moderate barrier to heterochromatin., In eukaryotic cells, highly condensed inactive/silenced chromatin has long been called “heterochromatin.” However, recent research suggests that such regions are in fact not fully transcriptionally silent and that there exists only a moderate access barrier to heterochromatin. To further investigate this issue, it is critical to elucidate the physical properties of heterochromatin such as its total density in live cells. Here, using orientation-independent differential interference contrast (OI-DIC) microscopy, which is capable of mapping optical path differences, we investigated the density of the total materials in pericentric foci, a representative heterochromatin model, in live mouse NIH3T3 cells. We demonstrated that the total density of heterochromatin (208 mg/ml) was only 1.53-fold higher than that of the surrounding euchromatic regions (136 mg/ml) while the DNA density of heterochromatin was 5.5- to 7.5-fold higher. We observed similar minor differences in density in typical facultative heterochromatin, the inactive human X chromosomes. This surprisingly small difference may be due to that nonnucleosomal materials (proteins/RNAs) (∼120 mg/ml) are dominant in both chromatin regions. Monte Carlo simulation suggested that nonnucleosomal materials contribute to creating a moderate access barrier to heterochromatin, allowing minimal protein access to functional regions. Our OI-DIC imaging offers new insight into the live cellular environments.

Purpose: The medial medullary lamina (MML) separates the medial globus pallidus (GPm) from the lateral. The aim of this study was to assess the changes in appearance of MML related to age using the phase difference-enhanced (PADRE) imaging and to determine whether PADRE can depict the MML in the patients with Parkinson’s disease (PD). Materials and Methods: We enrolled 20 patients with PD and 50 normal control subjects (NC). First, for the visualization of the MML in the NC, we compared the PADRE, susceptibility-weighted imaging (SWI)-like images and T2weighted imaging (WI) by using multiple comparison. The grading methods are as follows: grade 1; MML was not delineated, grade 2; less than half of MML was delineated, grade 3; more than half of MML was delineated and grade 4; whole MML was clearly delineated. We determined grade 3 and 4 as good depiction, delineating the GPm. Then, we evaluated patients with PD using the same method. Results: In NC, the delineation of MML was good in 84% of cases on PADRE, but only 34% of cases showed a good depiction on SWI-like images (average grading score 3.31 vs 2.11, P < 0.05). No MML was delineated in all cases on T2WI. Although younger subjects tended to show whole MML clearly, a part of MML tends to be obscured with age on PADRE. In patients with PD the depiction of MML on PADRE was also good in 90% of cases. Conclusion: The PADRE technique facilitates the depiction of the MML within globus pallidus (GP) on a broad range of age NC and patients with PD and it is superior to SWI-like images and T2WI.

The typical MRI findings in corticobasal degeneration (CBD), which have been described in previous reports, may be non-specific. We evaluated cerebral gyri (CG) using quantitative susceptibility mapping (QSM) images of patients with CBD, progressive supranuclear palsy (PSP), and Parkinson’s disease (PD) to determine the possibility of discriminating them on an individual basis. After reviewing the normal appearances on QSM on 16 healthy subjects, two radiologists assessed abnormal findings from 12 CBD, 14 PSP, and 30 PD patients. For conventional MRI, two radiologists independently reviewed typical CBD findings that have been previously reported. We also investigated three autopsy cases including one each of CBD, PSP, and PD to reveal the histopathological basis of MRI findings. CBD-specific findings included three layers; a higher susceptibility layer in superficial GM, a lower susceptibility layer, and a higher susceptibility layer in corticomedullary junction, with frequencies of 83% (10/12) in CBD, 21% (3/14) in PSP, and 0% (0/30) in PD patients. The typical CBD findings on conventional MRI were observed in only 42% (5/12) of CBD patients. Ferritin-positive microglia accumulated in the superficial gray matter (third cortical layer) and corticomedullary junction in CBD patients. The CG findings on QSM images may be more useful than those on conventional MRI for discriminating CBD from PD on an individual basis. Based on postmortem pathological data, cortical QSM hyperintensity might be an expression of ferritin-positive microglia.

Atypical heterochromatin forms on telomeres and correlates with ALT activities., Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heterochromatin stimulates transcriptional elongation at telomeres together with the recruitment of recombination factors, while disrupting heterochromatin had the opposite effect. Consistently, loss of SETDB1, disrupts telomeric heterochromatin and abrogates ALT. Thus, inhibiting telomeric heterochromatin formation in ALT cells might offer a new therapeutic approach to cancer treatment.

BackgroundHigher daytime cortisol levels because of a hyperactive hypothalamic–pituitary–adrenal axis have been reported in patients with major depressive disorder (MDD). The elevated glucocorticoids inhibit the proliferation of the oligodendrocytes that are responsible for myelinating the axons of white matter fibre tracts.AimsTo evaluate the relationship between white matter integrity and serum cortisol levels during a first depressive episode in drug-naive patients with MDD (MDD group) using a tract-based spatial statistics (TBSS) method.MethodThe MDD group (n= 29) and a healthy control group (n= 47) underwent diffusion tensor imaging (DTI) scans and an analysis was conducted using TBSS. Morning blood samples were obtained from both groups for cortisol measurement.ResultsCompared with the controls, the MDD group had significantly reduced fractional anisotropy values (PPConclusionsOur findings indicate that the elevated cortisol levels in the MDD group may injure the white matter integrity in the frontal–subcortical and frontal–limbic circuits.

Eukaryotic chromatin is a negatively charged long polymer composed of genomic DNA, histones, and various proteins. The charged property causes the chromatin structure to be dynamically changed. These dynamic changes are critical for genome functions such as gene expression because they directly govern the degree of DNA accessibility. Although the chromatin structure is not yet fully understood, currently increasing evidence suggests that chromatin has a dynamic liquid-like structure based on the 10-nm fiber but not the 30-nm fiber. This liquid-like property can drive the process of ‘scanning and targeting genomic DNA,’ which contributes to various genome functions including gene expression and DNA replication, repair, and recombination. Here, we discuss the liquid-like behavior of chromatin and its physical and biological relevance., This review comes from a themed issue on Genome architecture and expression, edited by Fred Berger and Pamela Geyer

Purpose: In multiple sclerosis (MS), a juxtacortical lesion at the border between the gray matter (GM) and subcortical white matter (WM) may often involve the GM. A recently developed, phase-weighted magnetic resonance imaging (MRI) technique “phase difference enhanced imaging (PADRE)” can delineate the GM and WM clearly due to the difference in myelin concentration. We evaluated whether PADRE is useful for the detection of GM involvement in the juxtacortical MS lesions. Methods: One neuroradiologist reviewed the conventional MRI in 13 MS patients and selected 48 juxtacortical lesions. At the first reading session with the conventional MRI alone (T2-weighted imaging, and two-dimensional and three-dimensional fluid-attenuated inversion recovery), two other neuroradiologists classified the lesions into three patterns according to their anatomical locations: (a) subcortical WM lesions involving the subcortical WM alone; (b) intracortical (IC) lesions involving the GM alone; (c) mixed GM/subcortical WM (mixed) lesions involving the both subcortical WM and GM. We defined the subcortical WM as a WM within a distance of 10 mm from inner edge of the GM. For the analyses, we excluded the white matter lesions further than 10 mm from inner edge of the GM. At the second reading session MRI and PADRE were available and the radiologists re-evaluated their prior classification. Results: At the first reading session, 27 lesions were classified as (a), 1 as (b), and 20 as (c). Therefore, a total of 21 lesions (44%) were judged to involve the GM. At the second reading session, the classification of 15 (31%) lesions changed; all 15 lesions were judged to involve the GM on the PADRE. Interobserver agreement (kappa value) was 0.84 for the first- and 0.95 for the second reading session. Conclusion: PADRE is useful for detecting GM involvement of the juxtacortical MS lesions.

We compared the precentral gyri (PG) on the PADRE of patients with amyotrophic lateral sclerosis (ALS) and healthy subjects (HSs) in order to determine whether it is possible to discriminate between ALS patients and HSs on an individual basis. First, two radiologists reviewed the appearance of the normal PG and that of ALS patients on PADRE in a non-blinded manner, and deviations from the appearance of the normal PG were recorded. Next, based on the presence of PG abnormalities on PADRE, we performed an observer performance study using 16 ALS patients and 16 HSs. The radiologists were able to consensually define the PG as abnormal on PADRE when a low-signal-intensity layer was observed in the gray matter of the PG; a three- or four-layer organization (zebra sign) was characterized by the low-signal-intensity layer. The observer performance study demonstrated that the sensitivity, specificity, and accuracy of PG abnormalities on PADRE for discriminating ALS patients from HSs were 94 %, 94 %, and 94 %, respectively, for reviewers 1 and 2. It was possible to discriminate between ALS patients and HSs based on the presence of PG abnormalities on PADRE, which may reflect upper motor neuron impairment in ALS. • PADRE reveals low-signal-intensity layer in the PG of ALS • By PADRE findings on PG, we can discriminate ALS from HSs • PADRE may be a useful method for detecting UMN impairment in ALS

BACKGROUND AND PURPOSE: Although the clinical importance of cortical microinfarcts has become well-recognized recently, the evolution of cortical microinfarcts on MR imaging is not fully understood. The aim of this study was to examine the temporal changes in acute cortical microinfarcts using susceptibility-weighted imaging and conventional MR imaging. MATERIALS AND METHODS: Patients with acute infarcts located in the cortical and/or juxtacortical region measuring ≤10 mm in axial diameter based on diffusion-weighted imaging who had a follow-up 3T MR imaging were retrospectively included in the study. All lesions did not show hypointensity on initial T2*WI. For cortical and/or juxtacortical microinfarcts detected on initial DWI, 2 neuroradiologists evaluated the follow-up MR imaging (T2WI, FLAIR, T2*WI, and SWI) and assessed lesion signal intensities and locations (cortical microinfarcts or microinfarcts with juxtacortical white matter involvement). RESULTS: On initial DWI, 2 radiologists observed 180 cortical and/or juxtacortical microinfarcts in 35 MR imaging examinations in 25 patients; on follow-up, the neuroradiologists identified 29 cortical microinfarcts (16%) on T2WI, 9 (5%) on FLAIR, 4 (2%) on T2*, and 97 (54%) on SWI. All cortical microinfarcts detected with any follow-up MR imaging showed hyperintensity on T2WI/FLAIR and/or hypointensity on T2*WI and SWI. CONCLUSIONS: SWI revealed conversion (paramagnetic susceptibility changes) of acute cortical microinfarcts, suggesting that a substantial number of cortical microinfarcts may contain hemorrhagic components.

Systemic lupus erythematosus (SLE) is related to vasculitis, which causes brain infarctions; however, the pathology of large cerebral vessels has not been fully established.To demonstrate the prevalence of vessel wall lesions (VWLs) in SLE patients using 3D vessel wall imaging and to assess the relationship between VWLs and brain infarctions.Retrospective.Sixty SLE patients and 50 healthy subjects (HS).Each subject underwent 3T MRI, which included 3D FSE PDWI (CUBE).For each of the 33 segments of the intracranial artery (internal carotid artery ∼ M3 segment of middle cerebral artery [MCA]), the VWLs were scored as either positive or negative, and the VWL score was calculated as the sum of the segments with VWLs. We also evaluated brain lesions on conventional MRI.We used logistic regression analyses to determine the clinical (serological test and cardiovascular risk factors) and imaging characteristics associated with infarctions in SLE patients.For the peripheral vessels such as MCA, VWLs were more common for SLE patients than for HS (43.3% versus 16.7% in M1 segment, 60.4% versus 16.7% in M2 segment, both P 0.01). There were 21 infarctions in 13 patients (21.7%), and the median VWL score was larger in the patients with infarctions than in those without (13 versus 6, P 0.01). Multivariate logistic regression analyses revealed a high VWL score ( ≥ 9) to be the only factor independently associated with the presence of infarctions (odds ratio: 10.1, 95% confidence interval: 1.01-101; P 0.049).We demonstrated a substantially high prevalence of VWLs among SLE patients, which were associated with brain infarctions.3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1237-1246.

Rationale and Objectives Quantitative susceptibility mapping (QSM) is a novel technique which allows determining the bulk magnetic susceptibility distribution of tissue in vivo from gradient echo magnetic resonance (MR) phase images. Our purpose was to evaluate if there is additional diagnostic value of QSM images in detecting the cortical gray matter involvement in multiple sclerosis (MS) patients. Materials and Methods Our institutional review board approved this study. Conventional MR imaging, including T2-weighted imaging and two- or three-dimensional fluid-attenuated inversion recovery images, and QSM imaging examinations were performed in 27 patients (19 male and eight female) with MS. Two radiologists (radiologists 1 and 2) assessed the MS lesions in the following 3 anatomic regions: intracortical, mixed white matter–gray matter (WM–GM), and juxtacortical regions. The numbers of lesions per region category were compared between conventional MR images with and without QSM images. Results For radiologists 1 and 2, QSM images identified 6 (50.0%) and 7 (50.0%) additional lesions that were not seen in the conventional MR images, respectively. In a lesion-by-lesion analysis, the substantial fraction (20 [25.3%] of 79 at radiologist 1, 22 [29.7%] of 74 at radiologist 2) of juxtacortical white matter lesions on the conventional MR images were scored as mixed WM–GM lesions with QSM images. Conclusions Our preliminary results suggest that the MR imaging with QSM may increase the sensitivity in cortical lesion detection in the MS brain and improved distinction between juxtacortical and mixed WM–GM lesions.

Catechol-O-methyltransferase (COMT) is a methylation enzyme engaged in the degradation of dopamine and noradrenaline by catalyzing the transfer of a methyl group from S-adenosylmethionine. An association was found between the Valine (Val) 108/158Methionine (Met) COMT polymorphism (rs4680) and major depressive disorder (MDD). The authors prospectively investigated the relationship between the Val108/158Met COMT genotype and voxel-based morphometry (VBM) findings for patients with first-episode and treatment-naïve MDD and healthy subjects (HS). Participants comprised 30 MDD patients and 48 age- and sex-matched HS who were divided according to the COMT genotype. Effects of diagnosis, COMT genotype, and the genotype-diagnosis interaction in relation to brain morphology in the Val/Met and Val/Val individuals were evaluated using a VBM analysis of high-resolution magnetic resonance imaging findings. Among the Val/Met individuals, the volume of the bilateral caudate was significantly smaller for MDD patients than for HS. In the Val/Val individuals, the caudate volume was comparable between MDD patients and HS. Significant genotype-diagnosis interaction effects on brain morphology were noted in the right caudate.