Fork coupling directs DNA replication elongation and termination.

DNA replication is initiated at multiple loci to ensure timely duplication of eukaryotic genomes. Sister replication forks progress bidirectionally, and replication terminates when two convergent forks encounter one another. To investigate the coordination of replication forks, we developed a replication-associated in situ HiC method to capture chromatin interactions involving nascent DNA. We identify more than 2000 fountain-like structures of chromatin contacts in human and mouse genomes, indicative of coupling of DNA replication forks. Replication fork interaction not only occurs between sister forks but also involves forks from two distinct origins to predetermine replication termination. Termination-associated chromatin fountains are sensitive to replication stress and lead to coupled forks-associated genomic deletions in cancers. These findings reveal the spatial organization of DNA replication forks within the chromatin context.

Cohesin maintains replication timing to suppress DNA damage on cancer genes.

Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism underlying its role in tumorigenesis is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks and 147 translocation hotspot genes, co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor disruption. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.

Application of electromagnetic disturbance technology in predicting ventriculoperitoneal shunt dependency after aneurysm-associated subarachnoid hemorrhage.

BACKGROUND: The aim of this study was to evaluate the predictive power of electromagnetic disturbance technology in patients with hydrocephalus after subarachnoid hemorrhage. METHODS: This prospective, observational cohort study was conducted at The First Affiliated Hospital of Zhengzhou University and Nanfang Hospital. A total of 155 patients with subarachnoid hemorrhage (SAH) were enrolled in this study. Disturbance coefficients were recorded using a continuous sinusoidal signal in real time after SAH. The patients were divided into two groups: hydrocephalus group (patients who underwent shunt insertion within a month after SAH) and non-hydrocephalus group (patients without need for a ventriculoperitoneal shunt). We used SPSS to draw a ROC Curve to assess the ability of disturbance coefficients to predict the probability of hydrocephalus. RESULTS: Hydrocephalus occurred in 37 patients after SAH. The average disturbance coefficient of patients with hydrocephalus decreased by 25.14±9.78, and the disturbance coefficient of patients with no hydrocephalus decreased by 6.58±10.10 (one aspect of the present invention is a system of non-invasively monitoring hydrocephalus, cerebral edema, and intracranial bleeding comprising of a source emitting electromagnetic waves to brain tissue, a detector detecting said wave that propagates through said tissue, a signal conditioning unit amplifying and filtering said wave, a quadrature detector estimating magnitude and phases of said wave, and a parameter estimator calculating the complex wave number, relative attenuation coefficient (RAC), relative phase shift (RPS), wave speed change (WSC), and travel-time difference (TTD) of said brain, and assessing status of hydrocephalus and cerebral edema). The difference was statistically significant (t=9.825, P<0.001). The decrease in disturbance coefficient can be used to predict the occurrence of hydrocephalus, and if the disturbance coefficient decreases by more than 15.5 (sensitivity, 92.37%; specificity, 86.49%), it can be used to indicate the occurrence of hydrocephalus. CONCLUSIONS: The disturbance coefficient can predict the occurrence of hydrocephalus. The greater decline of the disturbance coefficient, the greater probability of occurrence of intracranial hydrocephalus. Hydrocephalus can be early detected. However, the CT scan is necessary to confirm the occurrence of hydrocephalus. Early diagnosis and early treatment may improve the prognosis of patients with hydrocephalus after subarachnoid hemorrhage.