ReplicationDomain: a visualization tool and comparative database for genome-wide replication timing data

<p>Abstract</p> <p>Background</p> <p>Eukaryotic DNA replication is regulated at the level of large chromosomal domains (0.5–5 megabases in mammals) within which replicons are activated relatively synchronously. These domains replicate in a specific temporal order during S-phase and our genome-wide analyses of replication timing have demonstrated that this temporal order of domain replication is a stable property of specific cell types.</p> <p>Results</p> <p>We have developed ReplicationDomain <url>http://www.replicationdomain.org</url> as a web-based database for analysis of genome-wide replication timing maps (replication profiles) from various cell lines and species. This database also provides comparative information of transcriptional expression and is configured to display any genome-wide property (for instance, ChIP-Chip or ChIP-Seq data) via an interactive web interface. Our published microarray data sets are publicly available. Users may graphically display these data sets for a selected genomic region and download the data displayed as text files, or alternatively, download complete genome-wide data sets. Furthermore, we have implemented a user registration system that allows registered users to upload their own data sets. Upon uploading, registered users may choose to: (1) view their data sets privately without sharing; (2) share with other registered users; or (3) make their published or "in press" data sets publicly available, which can fulfill journal and funding agencies' requirements for data sharing.</p> <p>Conclusion</p> <p>ReplicationDomain is a novel and powerful tool to facilitate the comparative visualization of replication timing in various cell types as well as other genome-wide chromatin features and is considerably faster and more convenient than existing browsers when viewing multi-megabase segments of chromosomes. Furthermore, the data upload function with the option of private viewing or sharing of data sets between registered users should be a valuable resource for the scientific community.</p

Global Reorganization of Replication Domains During Embryonic Stem Cell Differentiation

DNA replication in mammals is regulated via the coordinate firing of clusters of replicons that duplicate megabase-sized chromosome segments at specific times during S-phase. Cytogenetic studies show that these “replicon clusters” coalesce as subchromosomal units that persist through multiple cell generations, but the molecular boundaries of such units have remained elusive. Moreover, the extent to which changes in replication timing occur during differentiation and their relationship to transcription changes has not been rigorously investigated. We have constructed high-resolution replication-timing profiles in mouse embryonic stem cells (mESCs) before and after differentiation to neural precursor cells. We demonstrate that chromosomes can be segmented into multimegabase domains of coordinate replication, which we call “replication domains,” separated by transition regions whose replication kinetics are consistent with large originless segments. The molecular boundaries of replication domains are remarkably well conserved between distantly related ESC lines and induced pluripotent stem cells. Unexpectedly, ESC differentiation was accompanied by the consolidation of smaller differentially replicating domains into larger coordinately replicated units whose replication time was more aligned to isochore GC content and the density of LINE-1 transposable elements, but not gene density. Replication-timing changes were coordinated with transcription changes for weak promoters more than strong promoters, and were accompanied by rearrangements in subnuclear position. We conclude that replication profiles are cell-type specific, and changes in these profiles reveal chromosome segments that undergo large changes in organization during differentiation. Moreover, smaller replication domains and a higher density of timing transition regions that interrupt isochore replication timing define a novel characteristic of the pluripotent state

Identification and characterization of SA/Scc3p subunits in the Xenopus and human cohesin complexes

Abstract. A multisubunit protein complex, termed cohesin, plays an essential role in sister chromatid cohesion in yeast and in Xenopus laevis cell-free extracts. We report here that two distinct cohesin complexes exist in Xenopus egg extracts. A 14S complex (x-cohesin SA1) contains XSMC1, XSMC3, XRAD21, and a newly identified subunit, XSA1. In a second 12.5S complex (x-cohesin SA2), XSMC1, XSMC3, and XRAD21 associate with a different subunit, XSA2. Both XSA1 and XSA2 belong to the SA family of mammalian proteins and exhibit similarity to Scc3p, a recently identified component of yeast cohesin. In Xenopus egg extracts, x-cohesin SA1 is predominant, whereas x-cohesin SA2 constitutes only a very minor population. Human cells have a similar pair of cohesin complexes, but the SA2-type is the dominant form in somatic tissue culture cells. Immunolocalization experiments suggest that chromatin association of cohesin SA1 and cohesin SA2 may be differentially regulated. Dissociation of x-cohesin SA1 from chromatin correlates with phosphorylation of XSA1 in the cell-free extracts. Purified cdc2-cyclin B can phosphorylate XSA1 in vitro and reduce the ability of x-cohesin SA1 to bind to DNA or chromatin. These results shed light on the mechanism by which sister chromatid cohesion is partially dissolved in early mitosis, far before the onset of anaphase, in vertebrate cells. Key words: Xenopus egg extract • sister chromatid cohesion • SMC proteins • chromosome structure • mitosi

Risk factors for blood vessel rupture during vascular access intervention therapy for hemodialysis patients.

Blood vessel rupture is a major complication associated with vascular access intervention therapy (VAIVT). However, information regarding the risk factors for ruptures related to VAIVT is limited. The purpose of this study was to investigate the risk factors for rupture during VAIVT. This was a single-center, retrospective observational study. Demographic, clinical, anatomical, and VAIVT procedure variables were reviewed and analyzed using multivariate logistic regression. The 211 patients included in the study underwent 628 VAIVT procedures from November 2019 to December 2021, and 20 blood vessel ruptures occurred. Patients with ruptures had significantly lower BMI (p = 0.043), shorter access vintage(p = 0.017), underwent VAIVT for the first time (p = 0.006), and had lower blood flow quantity (p = 0.005), lower brachial artery flow volume (p = 0.018), and higher resistance index (p = 0.011). The multivariate logistic regression revealed that receiving VAIVT for the first time (OR 5.95, 95%CI 1.01-34.84; p = 0.048) and high resistance index (OR 1.86, 95%CI 1.01-3.16; p = 0.02) were significantly associated with a high risk for rupture. Furthermore, receiver operating characteristic curve analysis to assess the sensitivity-specificity profiles of the resistance index for ruptures showed that the optimal threshold was 0.70 (sensitivity/specificity, 0.69/0.70). Heightened surveillance during vascular access intervention therapy is warranted, especially in patients undergoing VAIVT for the first time or patients with a high resistance index (> 0.70)

Hereditary cardiac amyloidosis associated with Pro24Ser transthyretin mutation: a case report

Abstract Background Transthyretin amyloidosis is a systemic disorder caused by extracellular deposition of insoluble amyloid fibrils in peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs. Hereditary transthyretin amyloidosis is an autosomal dominant disease. More than 120 mutations have been reported in the transthyretin gene with considerable phenotypic heterogeneity and geographic diversity. Among them, a sporadic case of hereditary transthyretin amyloidosis with cardiac-predominant phenotype is very rare, progressive, and potentially fatal if left undiagnosed. However, a clinical diagnosis of cardiac amyloidosis still remains challenging due to non-specific symptoms, and less sensitivity and specificity of medical examinations. Case presentation A 60-year-old Japanese man with a history of embolic stroke and hypertrophic cardiomyopathy visited our department for heart failure. The present case exhibited only cardiomyopathy without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome, polyneuropathy, or autonomic dysfunction. An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. Technetium pyrophosphate scintigraphy indicated marked diffuse myocardial uptake of technetium pyrophosphate, strongly suggesting transthyretin cardiac amyloidosis, which was firmly confirmed by a left ventricular endomyocardial biopsy. Genetic analysis demonstrated a transthyretin C70T (Pro24Ser) heterozygous mutation. Tafamidis, a transthyretin stabilizer, was started. His cardiac symptoms remained unchanged for 12 months. Conclusions Here we report the case of a patient with hereditary cardiac amyloidosis associated with a Pro24Ser mutation in transthyretin, which is the first case reported in Japan. Technetium pyrophosphate scintigraphy was extremely useful for definitive diagnosis. Thus, we propose that the nuclear imaging technique should be taken into account even for an exploratory diagnosis of transthyretin cardiac amyloidosis

Baseline clinical and biochemical characteristics of 628 patients receiving vascular access intervention therapy.

Baseline clinical and biochemical characteristics of 628 patients receiving vascular access intervention therapy.</p

Relevant to rupture and resistance index.

Blood vessel rupture is a major complication associated with vascular access intervention therapy (VAIVT). However, information regarding the risk factors for ruptures related to VAIVT is limited. The purpose of this study was to investigate the risk factors for rupture during VAIVT. This was a single-center, retrospective observational study. Demographic, clinical, anatomical, and VAIVT procedure variables were reviewed and analyzed using multivariate logistic regression. The 211 patients included in the study underwent 628 VAIVT procedures from November 2019 to December 2021, and 20 blood vessel ruptures occurred. Patients with ruptures had significantly lower BMI (p = 0.043), shorter access vintage(p = 0.017), underwent VAIVT for the first time (p = 0.006), and had lower blood flow quantity (p = 0.005), lower brachial artery flow volume (p = 0.018), and higher resistance index (p = 0.011). The multivariate logistic regression revealed that receiving VAIVT for the first time (OR 5.95, 95%CI 1.01–34.84; p = 0.048) and high resistance index (OR 1.86, 95%CI 1.01–3.16; p = 0.02) were significantly associated with a high risk for rupture. Furthermore, receiver operating characteristic curve analysis to assess the sensitivity-specificity profiles of the resistance index for ruptures showed that the optimal threshold was 0.70 (sensitivity/specificity, 0.69/0.70). Heightened surveillance during vascular access intervention therapy is warranted, especially in patients undergoing VAIVT for the first time or patients with a high resistance index (> 0.70).</div

Predictors of rupture based on multivariate logistic regression analysis.

Predictors of rupture based on multivariate logistic regression analysis.</p

Participants in research of blood vessels rupture during VAIVT.

Participants in research of blood vessels rupture during VAIVT.</p