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The ribosomal RNA (rDNA) gene repeats are essential housekeeping genes found in all organisms. A gene amplification system maintains large cluster(s) of tandemly repeated copies in the chromosome, with each species having a specific number of copies. Yeast has many untranscribed rDNA copies (extra copies), and we found that when they are lost, the cells become sensitive to DNA damage induced by mutagens. We show that this sensitivity is dependent on rDNA transcriptional activity, which interferes with cohesion between rDNA loci of sister chromatids. The extra rDNA copies facilitate condensin association and sister-chromatid cohesion, thereby facilitating recombinational repair. These results suggest that high concentrations of heavily transcribed genes are toxic to the cells, and therefore amplified genes, such as rDNA, have evolved.

The unbiased identification of proteins associated with specific loci is crucial for understanding chromatin-based processes. The proteomics of isolated chromatin fragment (PICh) method has previously been developed to purify telomeres and identify associated proteins. This approach is based on the affinity capture of endogenous chromatin segments by hybridization with oligonucleotide containing locked nucleic acids. However, PICh is only efficient with highly abundant genomic targets, limiting its applicability. Here we develop an approach for identifying factors bound to the promoter region of the ribosomal RNA genes that we call end-targeting PICh (ePICh). Using ePICh, we could specifically enrich the RNA polymerase I pre-initiation complex, including the selectivity factor 1. The high purity of the ePICh material allowed the identification of ZFP106, a novel factor regulating transcription initiation by targeting RNA polymerase I to the promoter. Our results demonstrate that ePICh can uncover novel proteins controlling endogenous regulatory elements in mammals. The identification of factors involved in eukaryotic DNA regulation at specific genomic regions distinct technical challenges. Here, the authors describe ePICh, a method that allows for the efficient isolation of chromatin factors associated with complex low abundance targets within the large genome of mammalian cells.

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.

Visual hallucinations (VH) occur commonly in Lewy body disease (LBD), including Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies. We aimed to use phase difference enhanced imaging (PADRE) to assess structural abnormalities of optic radiation (OR) in patients with Lewy body disease (LBD) concomitant with VH. Firstly, two radiologists reviewed the OR appearances in healthy subjects (HS) on PADRE. Next, based on the OR abnormalities, two reviewers assessed the PADRE images from 18 HS and 38 and 110 patients with LBD, with and without VH, respectively, in a blinded manner. Finally, all patients with LBD without VH were eventually followed up for at least 5 years after magnetic resonance imaging to determine the appearance of VH. The radiologists identified three layers, namely external sagittal stratum, internal sagittal stratum, and tapetum, in OR on the PADRE in HS. Moreover, they were able to consensually define the OR as abnormal when the layers were obscured and the disappearance of the cranial side. The sensitivity/specificity of abnormal OR for each case was 68%/81% (LBD with VH vs. LBD without VH). Furthermore, VH appeared in 12 of the 21 (57%) patients with LBD and abnormal OR during the follow-up period. However, no patients without abnormal OR reported VH. Patients with LBD and VH demonstrated the abnormal OR. This, in turn, might be a useful marker to distinguish the patients with VH from those without VH and HS. Moreover, abnormal OR on PADRE may precede the appearance of VH in LBD.

Tirabrutinib (TIR) is a second-generation, Bruton's tyrosine kinase inhibitor (BTKi) recently developed for the treatment of relapsed and refractory primary central nervous system lymphoma (PCNSL). However, little data are available regarding potential immunomodulatory effects of TIR on PCNSL due to its rarity and aggressive tumor behavior. Here, we report the first case of pseudo-progression (PSP) in a PCNSL patient treated with TIR. A 79-year-old woman had relapsed PCNSL with multiple tumor lesions in the lateral ventricles. A temporary tumor regression was observed following TIR administration. However, 7 months later, brain tumors regrew in the left lateral ventricle and in the choroid plexus of the right lateral ventricle, suggesting TIR-resistant disease progression. Despite the enlarged tumors, the patient remained asymptomatic, and re-remission was achieved by continuation of TIR monotherapy. Moreover, a durable remission for approximately 2 years was obtained without any additional therapy. This case shows that TIR can induce immunomodulatory reaction including PSP even in PCNSL, suggesting the importance of differential diagnosis of true disease progression and immune-mediated PSP based on careful clinical and radiological monitoring to avoid premature discontinuation of effective treatment.

The genes encoding ribosomal RNA are the most abundant in the eukaryotic genome. They reside in tandem repetitive clusters, in some cases totaling hundreds of copies. Due to their repetitive structure, ribosomal RNA genes (rDNA) are easily lost by recombination events within the repeated cluster. We previously identified a unique gene amplification system driven by unequal sister-chromatid recombination during DNA replication. The system compensates for such copy number losses, thus maintaining proper copy number. Here, through a genome-wide screen for genes regulating rDNA copy number, we found that the rtt109 mutant exhibited a hyper-amplification phenotype (∼3 times greater than the wild-type level). RTT109 encodes an acetyl transferase that acetylates lysine 56 of histone H3 and which functions in replication-coupled nucleosome assembly. Relative to unequal sister-chromatid recombination-based amplification (∼1 copy/cell division), the rate of the hyper-amplification in the rtt109 mutant was extremely high (>100 copies/cell division). Cohesin dissociation that promotes unequal sister-chromatid recombination was not observed in this mutant. During hyper-amplification, production level of extra-chromosomal rDNA circles (ERC) by intra-chromosomal recombination in the rDNA was reduced. Interestingly, during amplification, a plasmid containing an rDNA unit integrated into the rDNA as a tandem array. These results support the idea that tandem DNA arrays are produced and incorporated through rolling-circle-type replication. We propose that, in the rtt109 mutant, rDNA hyper-amplification is caused by uncontrolled rolling-circle-type replication.

Purpose 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. Methods 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. Results 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. Conclusions 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.

To determine whether any brain MR abnormalities, including enlarged perivascular spaces (EPVS), were associated with disease activity in systemic lupus erythematosus (SLE) as an inflammatory activity. One hundred and thirty SLE patients with normal MR findings were assessed. With regard to MRI abnormalities, patients with brain atrophy and mild white matter hyperintensity (WMH) on T2WI were not excluded. The disease activity was assessed using the SLEDAI and the BILAG scores. The imaging characteristics included centrum semiovale EPVS (CS- EPVS) and basal ganglia EPVS on T2WI, WMH, and brain atrophy. We used univariate and multivariate logistic regression analyses to determine the clinical (vascular risk factors and blood examinations) and imaging characteristics that were associated with the disease activity of SLE. High CS-EPVS to be the only factor that was independently associated with the severity of the SLEDAI and BILAG scores (odds ratio [OR] 5.77; 95% confidence interval [CI] 2.21–15.00; p < 0.001 for the SLEDAI, and OR 2.64; 95% CI 1.03–6.74; p = 0.042 for the BILAG score). The CS-EPVS in the SLE patients are associated with the systemic disease activity, suggesting that CS- EPVS may be indicative of the reactive changes of the white matter due to the inflammatory activity.

Legionnaires' disease is a form of atypical pneumonia that can present with neurological symptoms, such as headaches, seizures, and focal neurological abnormalities. We report the case of a male patient who developed impaired consciousness and recurrent seizures following pneumonia caused by . The patient received antibiotics and antiepileptic treatment and was discharged on hospital day 56. He was diagnosed with hippocampal sclerosis 10 months later. To our knowledge, this is the first reported case of hippocampal sclerosis following Legionnaires' disease globally. Clinicians should be aware of the risk of hippocampal sclerosis after Legionnaires' disease.

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, voxels within the hippocampus were entered into the ICA analysis to extract the structural covariance intra-networks within 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, two (one bilateral network and one 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.