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Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10 : MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients. Minichromosome maintenance protein 10 (MCM10) is critical for eukaryotic DNA replication. Here, by modelling MCM10 variants in human cell lines, the authors reveal a mechanism of MCM10-associated disease, finding that loss of MCM10 function constrains telomerase activity.

A hysteresis space vector pulse width modulation (SVPWM) reconfigurable fault-tolerant method for single-phase voltage source multi-level inverter with current tracking is proposed. Firstly, the influence of single switch open circuit fault and double switches open circuit fault on the voltage vector of the inverter is analyzed, and on this basis, the equivalent replacement of the voltage vector is obtained by using the topology reconstruction of the inverter, and the redundant voltage vectors with overlapping positions are preferred for equivalent replacement. If there are no coincident non-fault vectors, the other non-fault vectors with the closest position and effect are selected. The fault-tolerant method does not need the switching operation between the main power switching device and spare power switching device of the inverter, and can directly control the on–off process of the inverter reconfiguration unit through the driving signal of insulated gate bipolar translator (IGBT), which is simple and stable. Under the conditions of single switch open circuit and most double switches open circuit, the output current of the inverter can accurately track the reference current.

Covalent modification of histones is important in regulating chromatin dynamics and transcription 1 , 2 . One example of such modification is ubiquitination, which mainly occurs on histones H2A and H2B 3 . Although recent studies have uncovered the enzymes involved in histone H2B ubiquitination 4 , 5 , 6 and a ‘cross-talk’ between H2B ubiquitination and histone methylation 7 , 8 , the responsible enzymes and the functions of H2A ubiquitination are unknown. Here we report the purification and functional characterization of an E3 ubiquitin ligase complex that is specific for histone H2A. The complex, termed hPRC1L (human Polycomb repressive complex 1-like), is composed of several Polycomb-group proteins including Ring1, Ring2, Bmi1 and HPH2. hPRC1L monoubiquitinates nucleosomal histone H2A at lysine 119. Reducing the expression of Ring2 results in a dramatic decrease in the level of ubiquitinated H2A in HeLa cells. Chromatin immunoprecipitation analysis demonstrated colocalization of dRing with ubiquitinated H2A at the PRE and promoter regions of the Drosophila Ubx gene in wing imaginal discs. Removal of dRing in SL2 tissue culture cells by RNA interference resulted in loss of H2A ubiquitination concomitant with derepression of Ubx . Thus, our studies identify the H2A ubiquitin ligase, and link H2A ubiquitination to Polycomb silencing.

Polycomb group (PcG) proteins play important roles in maintaining the silent state of HOX genes. Recent studies have implicated histone methylation in long-term gene silencing. However, a connection between PcG-mediated gene silencing and histone methylation has not been established. Here we report the purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex. We demonstrate that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27). Using chromatin immunoprecipitation assays, we show that H3-K27 methylation colocalizes with, and is dependent on, E(Z) binding at an Ultrabithorax (Ubx) Polycomb response element (PRE), and that this methylation correlates with Ubx repression. Methylation on H3-K27 facilitates binding of Polycomb (PC), a component of the PRC1 complex, to histone H3 amino-terminal tail. Thus, these studies establish a link between histone methylation and PcG-mediated gene silencing.

By taking the blasting excavation of a deeply buried karst tunnel in the North Tianshan Mountains in China as research objects, the damage induced by blasting excavation and seepage characteristics of deep rock under high seepage pressure was investigated. The COMSOL Multiphysics® software was adopted to establish a simulation model for the blasting excavation of a deeply buried tunnel. By embedding the stress-damage-seepage multifield coupled constitutive relationship, the mechanism of the influences of factors including blasting load, geostress, and hydraulic pressure of karst caves on the blasting excavation-induced damage to, and seepage characteristic of, the surrounding rocks of the tunnel. The results indicate that blasting excavation in the karst tunnel triggers the damage of surrounding rocks, which consists of blasting-induced damage and unloading damage. The time-history curve of the variable for surrounding rock damage rises and consequently tends to a constant value. With the increases in blasting load, geostress, and hydraulic pressure of karst caves, the degree of damage to surrounding rocks is intensified; an increase in geostress will weaken the effect of blasting-induced damage to rock while increasing rock damage arising from unloading. Meanwhile, the degree of damage to the surrounding rock can affect the seepage velocity of water in the surrounding rock to a certain extent. A strong damage and seepage coupled effect occur in the blasting excavation process of the karst tunnel. The such coupled effect is strengthened little by little with the increases in the degree of surrounding rock damage and hydraulic pressures. The results are expected to provide theoretical guidance for hazard prevention and control of blasting excavation in karst tunnels under high geostress conditions.

Based on the lattice Boltzmann Method (LBM), a new moving boundary treatment is proposed by studying the influence of the moving boundary in a low-speed incompressible fluid. Simulating flow past a static cylinder, flow past a moving cylinder, and flow in a curved moving pipe shows that the LBM has high reliability and stability with moving boundary conditions. In order to reduce parallel computing time and take full advantage of the characteristics of the model, the solid grids are allocated according to the number of computing cores. Two parallel speedup ratios were tested, keeping the overall task volume unchanged to increase the number of cores and keeping the single-core task volume unchanged. In the first speedup ratio, the efficiency of the flow field calculation at 112 cores reached more than 80%. The second speedup ratio indicated that the proportion of communication in the program was tiny and suitable for large-scale parallel computing. The study of the moving boundary problem can effectively help solve the fluid-structure coupling problem. Due to the particularity of the model, it can be used to simulate the fluid-structure coupling problem of blood vessel flow effectively.

Natural killer (NK) cell deficiency (NKD) is a rare disease in which NK cell function is reduced, leaving affected individuals susceptible to repeated viral infections and cancer. Recently, a patient with NKD was identified carrying compound heterozygous variants of MCM10 ( minichromosome maintenance protein 10 ), an essential gene required for DNA replication, that caused a significant decrease in the amount of functional MCM10. NKD in this patient presented as loss of functionally mature late-stage NK cells. To understand how MCM10 deficiency affects NK cell development, we generated MCM10 heterozygous ( MCM10 +/− ) induced pluripotent stem cell (iPSC) lines. Analyses of these cell lines demonstrated that MCM10 was haploinsufficient, similar to results in other human cell lines. Reduced levels of MCM10 in mutant iPSCs was associated with impaired clonogenic survival and increased genomic instability, including micronuclei formation and telomere erosion. The severity of these phenotypes correlated with the extent of MCM10 depletion. Significantly, MCM10 +/− iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs). Although MCM10 +/− HSCs were able to give rise to lymphoid progenitors, these did not generate mature NK cells. The lack of mature NK cells coincided with telomere erosion, suggesting that NKD caused by these MCM10 variants arose from the accumulation of genomic instability including degradation of chromosome ends.

RAD18 is a conserved eukaryotic E3 ubiquitin ligase that promotes genome stability through multiple pathways. One of these is gap-filling DNA synthesis at active replication forks and in post-replicative DNA. RAD18 also regulates homologous recombination (HR) repair of DNA breaks; however, the current literature describing the contribution of RAD18 to HR in mammalian systems has not reached a consensus. To investigate this, we examined three independent RAD18-null human cell lines. Our analyses found that loss of RAD18 in HCT116, but neither hTERT RPE-1 nor DLD1 cell lines, resulted in elevated sister chromatid exchange, gene conversion, and gene targeting, i.e., HCT116 mutants were hyper-recombinogenic (hyper-rec). Interestingly, these phenotypes were linked to RAD18’s role in PCNA K164 ubiquitination, as HCT116 PCNAK164R/+ mutants were also hyper-rec, consistent with previous studies in rad18−/− and pcnaK164R avian DT40 cells. Importantly, the knockdown of UBC9 to prevent PCNA K164 SUMOylation did not affect hyper-recombination, strengthening the link between increased recombination and RAD18-catalyzed PCNA K164 ubiquitination, but not K164 SUMOylation. We propose that the hierarchy of post-replicative repair and HR, intrinsic to each cell type, dictates whether RAD18 is required for suppression of hyper-recombination and that this function is linked to PCNA K164 ubiquitination.

In this paper, an optical sensor based on a cadmium sulfide (CdS) nanobelt has been developed. The CdS nanobelt was synthesized by the vapor phase transportation (VPT) method. X-Ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) results revealed that the nanobelt had a hexagonal wurtzite structure of CdS and presented good crystal quality. A single nanobelt Schottky contact optical sensor was fabricated by the electron beam lithography (EBL) technique, and the device current-voltage results showed back-to-back Schottky diode characteristics. The photosensitivity, dark current and the decay time of the sensor were 4 × 104, 31 ms and 0.2 pA, respectively. The high photosensitivity and the short decay time were because of the exponential dependence of photocurrent on the number of the surface charges and the configuration of the back to back Schottky junctions.